JP7103952B2 - FGFR4 inhibitor, its manufacturing method and application - Google Patents

Description

The present invention belongs to the field of drug synthesis, and specifically relates to an FGFR4 inhibitor, a method for producing the same, and an application thereof.

The fibroblast growth factor receptor (FGFR) belongs to the receptor tyrosine kinase transmembrane receptor and contains four receptor subtypes, FGFR1, FGFR2, FGFR3 and FGFR4. FGFR regulates various functions such as cell proliferation, survival, differentiation and migration, and plays an important role in the development of the human body and each function of the adult body. FGFR exhibits abnormalities including gene amplification, mutation and overexpression in various human tumors and is an important target for targeted therapeutic studies of tumors.

FGFR4, a member of the FGFR receptor family, forms dimers on the cell membrane by binding to its ligand, fibroblast growth factor 19 (FGF19), and the formation of these dimers is in the cells of FGFR4 itself. Causes phosphorylation of key tyrosine residues in the cell, activating multiple intracellular signaling pathways that play important roles in cell proliferation, survival and anti-apoptosis. FGFR4 is overexpressed in many cancers and is a predictor of malignant tumor infiltration. Decreasing or reducing the expression of FGFR4 can reduce cell proliferation and promote apoptosis. Recently, more and more studies have shown that continued activation of the FGF19 / FGFR4 signaling pathway is a major carcinogenic factor leading to liver cancer in about one-third of patients with liver cancer. .. At the same time, FGFR4 expression or high expression is also closely associated with many other tumors such as gastric cancer, prostate cancer, skin cancer, ovarian cancer, lung cancer, breast cancer and colon cancer.

The incidence of liver cancer in China is the highest in the world, with new cases and deaths per year accounting for about half of the total number of liver cancers in the world. Currently, the incidence of liver cancer in China is about 28.7 / 100,000, with 394,770 new cases in 2012, and the third most serious malignant tumor with a mortality rate after gastric cancer and lung cancer. It becomes. The development of primary liver cancer is a multi-step, complex process with multiple factors that is highly invasive and has a poor prognosis. Surgical treatments such as liver resection and liver transplantation can improve survival in some patients, but only a limited number of patients can undergo surgery, and most patients have recurrence and metastasis after surgery. The prognosis is poor. Sorafenib is the only liver cancer treatment approved on the market, which can prolong overall survival by about 3 months and has insufficient therapeutic effect, so it is a new molecule-targeted liver cancer treatment. Development is urgent. Since FGFR4 is a major carcinogen of liver cancer, the development of its small molecule inhibitor has great potential for clinical application.

Currently, some FGFR inhibitors are in the clinical research stage as antitumor agents, but they are mainly inhibitors for FGFR1, 2 and 3, and their inhibition on FGFR4 activity is weak and FGFR1-3 inhibition is high. Has target-related side effects, such as phosphoricemia. Highly selective inhibitors of FGFR4 can effectively treat cancer diseases caused by abnormalities in the FGFR4 signaling pathway, and can avoid side effects such as hyperphosphatemia caused by inhibition of FGFR1-3, and are highly resistant to FGFR4. Selective small molecule inhibitors have great potential in the field of tumor-targeted therapies.

In the course of research, the inventor found an FGFR4 inhibitor having the structure of formula (I), and the compound series has a strong inhibitory effect on FGFR4 kinase activity and has a very high selectivity for cancer. In particular, it can be widely used in the production of therapeutic agents for liver cancer, gastric cancer, prostate cancer, skin cancer, ovarian cancer, lung cancer, breast cancer or colon cancer, and is expected to be developed as a next-generation FGFR4 inhibitor drug.

（式中、
Ｘ_１は－（ＣＲ_３Ｒ_４）ｍ_１－、Ｘ_２は－（ＣＲ_５Ｒ_６）ｍ_２－、Ｘ_３は－（ＣＲ_７Ｒ_８）ｍ_３－であり、
ＹはＯ又はＳから選ばれ、
ＺはＮＸ_４、Ｏ又はＳから選ばれ、
Ｘ_４は水素、重水素、Ｃ_１－８アルキル基、Ｃ_３－８シクロアルキル基又はハロ置換Ｃ_１－８アルキル基から選ばれ、
Ｒは水素、重水素、ハロゲン、ヒドロキシ基、メルカプト基、シアノ基、ニトロ基、アジド基、Ｃ_１－８アルキル基、ハロ置換Ｃ_１－８アルキル基、Ｃ_３－８シクロアルキル基、３－８員複素環基、３－８員複素環オキシ基、３－８員複素環チオ基、－Ｃ_０－８－Ｓ（Ｏ）_ｒＲ_９、－Ｃ_０－８－Ｏ－Ｒ_１０、－Ｃ_０－８－Ｃ（Ｏ）ＯＲ_１０、－Ｃ_０－８－Ｃ（Ｏ）Ｒ_１１、－Ｃ_０－８－Ｏ－Ｃ（Ｏ）Ｒ_１１、－Ｃ_０－８－ＮＲ_１２Ｒ_１３、－Ｃ_０－８－Ｃ（Ｏ）ＮＲ_１２Ｒ_１３、－Ｎ（Ｒ_１２）－Ｃ（Ｏ）Ｒ_１１又は－Ｎ（Ｒ_１２）－Ｃ（Ｏ）ＯＲ_１０から選ばれ、
Ｒ_１は水素、重水素、ハロゲン、ヒドロキシ基、メルカプト基、シアノ基、ニトロ基、アジド基、Ｃ_１－８アルキル基、Ｃ_２－８アルケニル基、Ｃ_２－８アルキニル基、Ｃ_３－８シクロアルキル基、３－８員複素環基、３－８員複素環オキシ基、３－８員複素環チオ基、－Ｃ_０－８－Ｓ（Ｏ）_ｒＲ_９、－Ｃ_０－８－Ｏ－Ｒ_１０、－Ｃ_０－８－Ｃ（Ｏ）ＯＲ_１０、－Ｃ_０－８－Ｃ（Ｏ）Ｒ_１１、－Ｃ_０－８－Ｏ－Ｃ（Ｏ）Ｒ_１１、－Ｃ_０－８－ＮＲ_１２Ｒ_１３、－Ｃ_０－８－Ｃ（Ｏ）ＮＲ_１２Ｒ_１３、－Ｎ（Ｒ_１２）－Ｃ（Ｏ）Ｒ_１１又は－Ｎ（Ｒ_１２）－Ｃ（Ｏ）ＯＲ_１０から選ばれ、
場合によって、さらに、ハロゲン、ヒドロキシ基、アルキル基、アルコキシ基、ハロ置換Ｃ_１－８アルキル基、Ｃ_３－８シクロアルキル基、３－８員複素環基、３－８員複素環オキシ基、３－８員複素環チオ基、Ｃ_１－８アルコキシ置換３－８員ヘテロアリール基、－Ｃ_０－８－Ｓ（Ｏ）_ｒＲ_９、－Ｃ_０－８－Ｏ－Ｒ_１０、－Ｃ_０－８－Ｃ（Ｏ）ＯＲ_１０、－Ｃ_０－８－Ｃ（Ｏ）Ｒ_１１、－Ｃ_０－８－Ｏ－Ｃ（Ｏ）Ｒ_１１、－Ｃ_０－８－ＮＲ_１２Ｒ_１３、－Ｃ_０－８－Ｃ（Ｏ）ＮＲ_１２Ｒ_１３、－Ｎ（Ｒ_１２）－Ｃ（Ｏ）Ｒ_１１又は－Ｎ（Ｒ_１２）－Ｃ（Ｏ）ＯＲ_１０から選ばれる１つ又は複数の置換基によって置換されてもよく、
Ｒ_２はハロゲン、ヒドロキシ基、メルカプト基、シアノ基、チオシアノ基、ニトロ基、アジド基、Ｃ_１－８アルキル基、Ｃ_２－８アルケニル基、Ｃ_２－８アルキニル基、Ｃ_３－８シクロアルキル基、３－８員複素環基、Ｃ_１－８アルキル基酸素基、Ｃ_３－８シクロアルコキシ基又は３－８員複素環オキシ基から選ばれ、
場合によって、さらに、ハロゲン、ヒドロキシ基、メルカプト基、シアノ基、ニトロ基、アジド基、Ｃ_１－８アルキル基、Ｃ_２－８アルケニル基、Ｃ_２－８アルキニル基、ハロ置換Ｃ_１－８アルキル基、Ｃ_３－８シクロアルキル基、３－８員複素環基、３－８員複素環オキシ基、３－８員複素環チオ基、Ｃ_５－１０アリール基、Ｃ_５－１０アリールオキシ基、Ｃ_５－１０アリールチオ基、５－１０員ヘテロアリール基、５－１０員ヘテロアリールオキシ基、５－１０員ヘテロアリールチオ基、－Ｃ_０－８－Ｓ（Ｏ）_ｒＲ_９、－Ｃ_０－８－Ｏ－Ｒ_１０、－Ｃ_０－８－Ｃ（Ｏ）ＯＲ_１０、－Ｃ_０－８－Ｃ（Ｏ）Ｒ_１１、－Ｃ_０－８－Ｏ－Ｃ（Ｏ）Ｒ_１１、－Ｃ_０－８－ＮＲ_１２Ｒ_１３、－Ｃ_０－８－Ｃ（Ｏ）ＮＲ_１２Ｒ_１３、－Ｎ（Ｒ_１２）－Ｃ（Ｏ）Ｒ_１１又は－Ｎ（Ｒ_１２）－Ｃ（Ｏ）ＯＲ_１０から選ばれる１つ又は複数の置換基によって置換されてもよく、
Ｒ_３、Ｒ_４、Ｒ_５、Ｒ_６、Ｒ_７、Ｒ_８はそれぞれ独立して水素、重水素、ハロゲン、Ｃ_１－８アルキル基、Ｃ_２－８アルケニル基、Ｃ_２－８アルキニル基、ハロ置換Ｃ_１－８アルキル基、Ｃ_３－８シクロアルキル基、３－８員複素環基、Ｃ_１－８アルコキシ基、ハロ置換Ｃ_１－８アルコキシ基、Ｃ_３－８シクロアルコキシ基又は３－８員複素環オキシ基から選ばれ、
又は、Ｒ_３及びＲ_４、Ｒ_５及びＲ_６、Ｒ_７及びＲ_８は、直接結合される炭素原子とともに３－５員シクロアルキル基又は３－５員複素環アルキル基を形成し、
Ｒ_９は水素、重水素、Ｃ_１－８アルキル基、Ｃ_２－８アルケニル基、Ｃ_３－８シクロアルキル基、３－８員複素環基、ハロ置換Ｃ_１－８アルキル基、フェニル基、ｐ－メチル基フェニル基、アミノ基、モノＣ_１－８アルキルアミノ基、ジＣ_１－８アルキルアミノ基又はＣ_１－８アルカノイルアミノ基から選ばれ、
Ｒ_１０は水素、重水素、Ｃ_１－８アルキル基、Ｃ_３－８シクロアルキル基、Ｃ_５－１０アリール基、３－８員複素環基、ハロ置換Ｃ_１－８アルキル基又はヒドロキシ置換Ｃ_１－８アルキル基から選ばれ、
Ｒ_１１は水素、重水素、Ｃ_１－８アルキル基、Ｃ_１－８アルコキシ基、Ｃ_３－８シクロアルキル基、Ｃ_３－８シクロアルコキシ基、ハロ置換Ｃ_１－８アルキル基、ハロ置換Ｃ_１－８アルコキシ基、ヒドロキシ置換Ｃ_１－８アルキル基又はヒドロキシ置換Ｃ_１－８アルコキシ基から選ばれ、
Ｒ_１２、Ｒ_１３はそれぞれ独立して水素、重水素、Ｃ_１－８アルキル基、Ｃ_１－８アルコキシＣ_１－８アルキル基、Ｃ_３－８シクロアルキルＣ_１－８アルキル基、Ｃ_２－８アルケニル基、Ｃ_２－８アルキニル基、Ｃ_３－８シクロアルキル基、３－８員複素環基、Ｃ_５－１０アリール基、５－１０員ヘテロアリール基又はＣ_１－８アルカノイル基から選ばれ、
ｍ_１、ｍ_２、ｍ_３はそれぞれ独立して０、１又は２から選ばれ、ただしｍ_１、ｍ_２は同時に０ではならず、
ｒは０、１又は２である。） A first aspect of the present invention provides a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

(During the ceremony
X ₁ is-(CR ₃ R ₄ ) m _1- , X ₂ is-(CR ₅ R ₆ ) m _2- , X ₃ is-(CR ₇ R ₈ ) m _3- .
Y is selected from O or S,
Z is selected from NX ₄ , O or S,
X ₄ is selected from hydrogen, deuterium, C _1-8 alkyl groups, C _3-8 cycloalkyl groups or halo-substituted C _1-8 alkyl groups.
R is hydrogen, dehydrogen, halogen, hydroxy group, mercapto group, cyano group, nitro group, azide group, C _1-8 alkyl group, halo-substituted C _1-8 alkyl group, C _3-8 cycloalkyl group, 3- 8-membered heterocyclic group, 3-8-membered heterocyclic oxy group, 3-8-membered heterocyclic thio group, -C _0-8 -S (O) _r R ₉ , -C _0-8 -OR ₁₀ ,- C _0-8 -C (O) OR ₁₀ , -C _0-8 -C (O) R ₁₁ , -C _0-8 -OC (O) R ₁₁ , -C _0-8 -NR ₁₂ R ₁₃ , -C _0-8 -C (O) NR ₁₂ R ₁₃ , -N (R ₁₂ ) -C (O) R ₁₁ or -N (R ₁₂ ) -C (O) OR ₁₀
R ₁ is hydrogen, heavy hydrogen, halogen, hydroxy group, mercapto group, cyano group, nitro group, azide group, C _1-8 alkyl group, C _2-8 alkenyl group, C _2-8 alkynyl group, C _3-8 . Cycloalkyl group, 3-8 membered heterocyclic group, 3-8 membered heterocyclic oxy group, 3-8 membered heterocyclic thio group, -C _0-8 -S (O) _r R ₉ , -C _0-8- OR _{10, -C 0-8-C (O) OR 10 , -C 0-8 - C} (O) R ₁₁ , -C _0-8 -OC (O) R ₁₁ , -C _0- From ₈ -NR ₁₂ R ₁₃ , -C _0-8 -C (O) NR ₁₂ R ₁₃ , -N (R ₁₂ ) -C (O) R ₁₁ or -N (R ₁₂ ) -C (O) OR ₁₀ . Chosen,
In some cases, further, halogen, hydroxy group, alkyl group, alkoxy group, halo-substituted C _1-8 alkyl group, C _3-8 cycloalkyl group, 3-8 member heterocyclic group, 3-8 member heterocyclic oxy group, 3-8-membered heterocyclic thio group, C _1-8 alkoxy-substituted 3-8-membered heteroaryl group, -C _0-8 -S (O) _r R ₉ , -C _0-8 -OR ₁₀ , -C _0-8 -C (O) OR ₁₀ , -C _0-8 -C (O) R ₁₁ , -C _0-8 -OC (O) R ₁₁ , -C _0-8 -NR ₁₂ R ₁₃ , One or more selected from -C _0-8- C (O) NR ₁₂ R ₁₃ , -N (R ₁₂ ) -C (O) R ₁₁ or -N (R ₁₂ ) -C (O) OR ₁₀ . May be substituted with substituents
R ₂ is halogen, hydroxy group, mercapto group, cyano group, thiocyano group, nitro group, azide group, C _1-8 alkyl group, C _2-8 alkenyl group, C _2-8 alkynyl group, C _3-8 cycloalkyl. Selected from groups, 3-8 membered heterocyclic groups, C _1-8 alkyl groups oxygen groups, C _3-8 cycloalkoxy groups or 3-8 membered heterocyclic oxy groups.
In some cases, further, halogen, hydroxy group, mercapto group, cyano group, nitro group, azide group, C _1-8 alkyl group, C _2-8 alkenyl group, C _2-8 alkynyl group, halo-substituted C _1-8 alkyl. Group, C _3-8 cycloalkyl group, 3-8 member heterocyclic group, 3-8 member heterocyclic oxy group, 3-8 member heterocyclic thio group, C _5-10 aryl group, C _5-10 aryloxy group , C _5-10 arylthio group, 5-10 member heteroaryl group, 5-10 member heteroaryloxy group, 5-10 member heteroarylthio group, -C _0-8 -S (O) _r R ₉ , -C _0-8 -O-R ₁₀ , -C _0-8 -C (O) OR ₁₀ , -C _0-8 -C (O) R ₁₁ , -C _0-8 -OC (O) R ₁₁ , -C _0-8- NR ₁₂ R ₁₃ , -C _0-8 -C (O) NR ₁₂ R ₁₃ , -N (R ₁₂ ) -C (O) R ₁₁ or -N (R ₁₂ ) -C (O) ) It may be substituted with one or more substituents selected from OR ₁₀ .
R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , and R ₈ are independently hydrogen, dehydrogen, halogen, C _1-8 alkyl group, C _2-8 alkoxy group, C _2-8 alkynyl group, respectively. Halo-substituted C _1-8 alkyl group, C _3-8 cycloalkyl group, 3-8 member heterocyclic group, C _1-8 alkoxy group, halo-substituted C _1-8 alkoxy group, C _3-8 cycloalkoxy group or 3 Selected from -8-membered heterocyclic oxy groups,
Alternatively, R3 and _R4 , R5 and R6, _R7 and R8 form a _{3-5 -} membered cycloalkyl group or a _{3-5 -} membered heterocyclic alkyl group together with the directly bonded carbon atom.
R ₉ is hydrogen, dehydrogen, C _1-8 alkyl group, C _2-8 alkenyl group, C _3-8 cycloalkyl group, 3-8 member heterocyclic group, halo-substituted C _1-8 alkyl group, phenyl group, p-methyl group Selected from phenyl group, amino group, mono C _1-8 alkyl amino group, di C _1-8 alkyl amino group or C _1-8 alkanoyl amino group,
R ₁₀ is hydrogen, deuterium, C _1-8 alkyl group, C _3-8 cycloalkyl group, C _5-10 aryl group, 3-8 member heterocyclic group, halo-substituted C _1-8 alkyl group or hydroxy-substituted C. Selected from _1-8 alkyl groups,
R ₁₁ is hydrogen, dehydrogen, C _1-8 alkyl group, C _1-8 alkoxy group, C _3-8 cycloalkyl group, C _3-8 cycloalkoxy group, halo-substituted C _1-8 alkyl group, halo-substituted C. Selected from _1-8 Alkoxy Group, Hydroxy Substituted C _1-8 Alkyl Group or Hydroxy Substituted C _1-8 Alkoxy Group
R ₁₂ and R ₁₃ are independently hydrogen, heavy hydrogen, C _1-8 alkyl group, C _1-8 alkoxy C _1-8 alkyl group, C _3-8 cycloalkyl C _1-8 alkyl group, C _2- Select from ₈ -alkenyl group, C _2-8 alkynyl group, C _3-8 cycloalkyl group, 3-8 member heterocyclic group, C _5-10 aryl group, 5-10 member heteroaryl group or C _1-8 alkanoyl group. Re,
m ₁ , m ₂ , and m ₃ are independently selected from 0, 1 or 2, but m ₁ , m ₂ cannot be 0 at the same time.
r is 0, 1 or 2. )

（式中、Ａ_１は結合、ＮＸ_４、Ｏ又はＳから選ばれ、
Ｂ_１は結合、Ｏ又は環から選ばれ、前記環はＣ_３－８シクロアルキル基、３－８員複素環基、Ｃ_３－８シクロアルキルＣ_１－８アルキル基、Ｃ_５－１０アリール基又は５－１０員ヘテロアリール基から選ばれ、
Ｒは水素、重水素、ハロゲン、ヒドロキシ基、メルカプト基、シアノ基、ニトロ基、アジド基、Ｃ_１－８アルキル基、ハロ置換Ｃ_１－８アルキル基、Ｃ_３－８シクロアルキル基又は３－８員複素環基から選ばれ、
Ｒ_１４は水素、ハロゲン、Ｃ_１－８アルキル基、ハロ置換Ｃ_１－８アルキル基、Ｃ_１－８アルコキシ基、Ｃ_３－８シクロアルキル基、３－８員複素環基、３－８員複素環オキシ基、３－８員複素環チオ基、－Ｃ_０－８－Ｓ（Ｏ）_ｒＲ_９、－Ｃ_０－８－Ｏ－Ｒ_１０、－Ｃ_０－８－Ｃ（Ｏ）ＯＲ_１０、－Ｃ_０－８－Ｃ（Ｏ）Ｒ_１１、－Ｃ_０－８－Ｏ－Ｃ（Ｏ）Ｒ_１１、－Ｃ_０－８－ＮＲ_１２Ｒ_１３、－Ｃ_０－８－Ｃ（Ｏ）ＮＲ_１２Ｒ_１３、－Ｎ（Ｒ_１２）－Ｃ（Ｏ）Ｒ_１１又は－Ｎ（Ｒ_１２）－Ｃ（Ｏ）ＯＲ_１０から選ばれ
Ｒ_１５、Ｒ_１６はそれぞれ独立して水素、ハロゲン、ヒドロキシ基、アルキル基、ハロ置換Ｃ_１－８アルキル基、Ｃ_３－８シクロアルキル基、３－８員複素環基、３－８員複素環オキシ基、３－８員複素環チオ基、－Ｃ_０－８－Ｓ（Ｏ）_ｒＲ_９、－Ｃ_０－８－Ｏ－Ｒ_１０、－Ｃ_０－８－Ｃ（Ｏ）ＯＲ_１０、－Ｃ_０－８－Ｃ（Ｏ）Ｒ_１１、－Ｃ_０－８－Ｏ－Ｃ（Ｏ）Ｒ_１１、－Ｃ_０－８－ＮＲ_１２Ｒ_１３、－Ｃ_０－８－Ｃ（Ｏ）ＮＲ_１２Ｒ_１３、－Ｎ（Ｒ_１２）－Ｃ（Ｏ）Ｒ_１１又は－Ｎ（Ｒ_１２）－Ｃ（Ｏ）ＯＲ_１０から選ばれ、
又はＲ_１５、Ｒ_１６は、直接結合される炭素原子とともにシクロアルキル基又は複素環基を形成し、前記アルキル基又は複素環基は場合によって、さらに、Ｃ_１－８アルキル基、Ｃ_１－８ハロアルキル基、ハロゲン、ヒドロキシ基、Ｃ_１－８アルコキシ基及びＣ_１－８ヒドロキシアルキル基から選ばれる１つ又は複数の置換基によって置換されてもよく、
ｎは０－４であり、
Ｚ、Ｙ、Ｘ_１－Ｘ_３、Ｒは式（Ｉ）化合物に記載のとおりである。） Further, as a preferred form, the compound of the formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the compounds of the following formula (II).

(In the formula, A ₁ is selected from bond, NX ₄ , O or S,
B ₁ is selected from bond, O or ring, the ring being a C _3-8 cycloalkyl group, a 3-8 member heterocyclic group, a C _3-8 cycloalkyl C _1-8 alkyl group, a C _5-10 aryl group. Or selected from 5-10 member heteroaryl groups,
R is hydrogen, heavy hydrogen, halogen, hydroxy group, mercapto group, cyano group, nitro group, azide group, C _1-8 alkyl group, halo-substituted C _1-8 alkyl group, C _3-8 cycloalkyl group or 3- Selected from 8-membered heterocyclic groups,
R ₁₄ is hydrogen, halogen, C _1-8 alkyl group, halo-substituted C _1-8 alkyl group, C _1-8 alkoxy group, C _3-8 cycloalkyl group, 3-8 member heterocyclic group, 3-8 member. Heterocyclic oxy group, 3-8 member heterocyclic thio group, -C _0-8 -S (O) _r R ₉ , -C _0-8 -OR ₁₀ , -C _0-8 -C (O) OR ₁₀ , -C _0-8 -C (O) R ₁₁ , -C _0-8 -OC (O) R ₁₁ , -C _0-8 -NR ₁₂ R ₁₃ , -C _0-8 -C (O) ) NR ₁₂ R ₁₃ , -N (R ₁₂ ) -C (O) R ₁₁ or -N (R ₁₂ ) -C (O) OR ₁₀ , R ₁₅ and R ₁₆ are independently hydrogen, halogen, Hydroxy group, alkyl group, halo-substituted C _1-8 alkyl group, C _3-8 cycloalkyl group, 3-8 member heterocyclic group, 3-8 member heterocyclic oxy group, 3-8 member heterocyclic thio group,- C _0-8 -S (O) _r R ₉ , -C _0-8 -OR ₁₀ , -C _0-8 -C (O) OR ₁₀ , -C _0-8 -C (O) R ₁₁ , -C _0-8 -OC (O) R ₁₁ , -C _0-8 -NR ₁₂ R ₁₃ , -C _0-8 -C (O) NR ₁₂ R ₁₃ , -N (R ₁₂ ) -C ( O) R ₁₁ or -N (R ₁₂ ) -C (O) OR ₁₀ selected from
Alternatively, R ₁₅ and R ₁₆ form a cycloalkyl group or a heterocyclic group together with a carbon atom to be directly bonded, and the alkyl group or the heterocyclic group may further form a C _1-8 alkyl group or a C _1-8 . It may be substituted with one or more substituents selected from haloalkyl groups, halogens, hydroxy groups, C _1-8 alkoxy groups and C _1-8 hydroxyalkyl groups.
n is 0-4,
Z, Y, X1 _- X3 _, R are as described in the compound of formula (I). )

Further, as a preferred form, in the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, R is selected from hydrogen or fluorine and R ₂ is selected from a cyano group or a thiocyano group.
B ₁ is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, an oxetanyl group, a thietanyl group, an azetidinyl group, a furanyl group, a thienyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a pyridyl group, an oxazolyl group, a thiazolyl group, a tetrahydrofuranyl group, Selected from a tetrahydrothienyl group, a tetrahydropyrrrolyl group, a tetrahydroimidazolyl group, a tetrahydropyranyl group, a piperazinyl group or a morpholinyl group,
R ₁₄ is hydrogen, fluorine, chlorine, methoxy group, ethoxy group, trifluoromethyl group, cyclopropyl group, -C _0-8 -OR ₁₀ , -C _0-8 -C (O) OR ₁₀ , -C. Selected from _0-8 -C (O) R ₁₁ or -C _0-8 -OC (O) R ₁₁
Preferably, when -R ₁₄ and-(CR ₁₅ R ₁₆ ) _n -are bonded to the adjacent ring atom of B ₁ , the stereoisomers are (R) -R ₁₄ , (S)-(CR ₁₅ R). ₁₆ ) _n- , (S) -R ₁₄ , (R)-(CR ₁₅ R ₁₆ ) _n- , (R) -R ₁₄ , (R)-(CR ₁₅ R ₁₆ ) _n- or (S) -R ₁₄ , including the conformation of (S)-(CR ₁₅ R ₁₆ ) _n-
Preferably, when -R ₁₄ and-(CR ₁₅ R ₁₆ ) _n- are attached to the common ring atom of B ₁ , the stereoisomers are (R) -R ₁₄ , (S)-(CR ₁₅ R). ₁₆ ) Including the conformation of _n- or (S) -R ₁₄ , (R)-(CR ₁₅ R ₁₆ ) _n- .
Z, Y, X ₁ -X ₃ , A ₁ , R ₁ and R _15-16 are as described in the compound of formula (I).

As the most preferable form, the compound of the formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the following compounds.

Further, as a preferred form, in the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof.
R is selected from hydrogen or fluorine, R ₂ is selected from cyano or thiocyano groups, B ₁ is selected from phenyl or pyridyl groups.
R ₁₄ is fluorine, chlorine, methoxy group, ethoxy group, trifluoromethyl group, cyclopropyl group, -C _0-8 -OR ₁₀ , -C _0-8 -C (O) OR ₁₀ , -C _{0- 8} -C (O) R ₁₁ , -C _0-8 -OC (O) R ₁₁ , -C _0-8 -NR ₁₂ R ₁₃ , -C _0-8 -C (O) NR ₁₂ R ₁₃ , Selected from -N (R ₁₂ ) -C (O) R ₁₁ or -N (R ₁₂ ) -C (O) OR ₁₀
n is chosen from 0 or 1
More preferably, when -R ₁₄ and -A _1- are bonded to the ring-adjacent carbon atom of benzene, the stereoisomers are (R) -R ₁₄ , (S) -A _1- , (S)-. Includes the conformation of R ₁₄ , (R) -A _1- , (R) -R ₁₄ , (R) -A _1- or (S) -R ₁₄ , (S) -A _1- .
Z, Y, X ₁ -X ₃ , A ₁ , R ₁ and R _15-16 are as described in the compound of formula (I).

As the most preferable form, the compound of the formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the following compounds.

（式中、Ａ_２は結合、ＮＸ_４、Ｏ又はＳから選ばれ、
Ｂ_２はＣ_１－８アルキル基、Ｃ_１－８アルコキシ基、Ｃ_１－８アルコキシＣ_１－８アルキル基から選ばれ、
Ｒは水素、重水素、ハロゲン、ヒドロキシ基、メルカプト基、シアノ基、ニトロ基、アジド基、Ｃ_１－８アルキル基、ハロ置換Ｃ_１－８アルキル基、Ｃ_３－８シクロアルキル基又は３－８員複素環基から選ばれ、
Ｒ_１７は水素、Ｃ_１－８アルキル基、ハロゲン、ハロ置換Ｃ_１－８アルキル基、Ｃ_３－８シクロアルキル基、３－８員複素環基、３－８員複素環オキシ基、３－８員複素環チオ基、－Ｃ_０－８－Ｓ（Ｏ）_ｒＲ_９、－Ｃ_０－８－Ｏ－Ｒ_１０、－Ｃ_０－８－Ｃ（Ｏ）ＯＲ_１０、－Ｃ_０－８－Ｃ（Ｏ）Ｒ_１１、－Ｃ_０－８－Ｏ－Ｃ（Ｏ）Ｒ_１１、－Ｃ_０－８－ＮＲ_１２Ｒ_１３、－Ｃ_０－８－Ｃ（Ｏ）ＮＲ_１２Ｒ_１３、－Ｎ（Ｒ_１２）－Ｃ（Ｏ）Ｒ_１１又は－Ｎ（Ｒ_１２）－Ｃ（Ｏ）ＯＲ_１０から選ばれ、
Ｒ_１８、Ｒ_１９はそれぞれ独立してハロゲン、ヒドロキシ基、アルキル基、ハロ置換Ｃ_１－８アルキル基、Ｃ_３－８シクロアルキル基、３－８員複素環基、３－８員複素環オキシ基、３－８員複素環チオ基、－Ｃ_０－８－Ｓ（Ｏ）_ｒＲ_９、－Ｃ_０－８－Ｏ－Ｒ_１０、－Ｃ_０－８－Ｃ（Ｏ）ＯＲ_１０、－Ｃ_０－８－Ｃ（Ｏ）Ｒ_１１、－Ｃ_０－８－Ｏ－Ｃ（Ｏ）Ｒ_１１、－Ｃ_０－８－ＮＲ_１２Ｒ_１３、－Ｃ_０－８－Ｃ（Ｏ）ＮＲ_１２Ｒ_１３、－Ｎ（Ｒ_１２）－Ｃ（Ｏ）Ｒ_１１又は－Ｎ（Ｒ_１２）－Ｃ（Ｏ）ＯＲ_１０から選ばれ、
又はＲ_１８、Ｒ_１９は、直接結合される炭素原子とともにシクロアルキル基又は複素環基を形成し、前記アルキル基又は複素環基は場合によって、さらに、Ｃ_１－８アルキル基、Ｃ_１－８ハロアルキル基、ハロゲン、ヒドロキシ基、Ｃ_１－８アルコキシ基及びＣ_１－８ヒドロキシアルキル基から選ばれる１つ又は複数の置換基によって置換されてもよく、
ｎは０－４である。） Further, as a preferred form, the compound of the formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the compounds of the following formula (III).

(In the formula, A ₂ is selected from bond, NX ₄ , O or S,
B ₂ is selected from a C _1-8 alkyl group, a C _1-8 alkoxy group, and a C _1-8 alkoxy C _1-8 alkyl group.
R is hydrogen, heavy hydrogen, halogen, hydroxy group, mercapto group, cyano group, nitro group, azide group, C _1-8 alkyl group, halo-substituted C _1-8 alkyl group, C _3-8 cycloalkyl group or 3- Selected from 8-membered heterocyclic groups,
R ₁₇ is hydrogen, C _1-8 alkyl group, halogen, halo-substituted C _1-8 alkyl group, C _3-8 cycloalkyl group, 3-8 member heterocyclic group, 3-8 member heterocyclic oxy group, 3- 8-membered heterocyclic thio group, -C _0-8 -S (O) _r R ₉ , -C _0-8 -OR ₁₀ , -C _0-8 -C (O) OR ₁₀ , -C _0-8 -C (O) R ₁₁ , -C _0-8 -OC (O) R ₁₁ , -C _0-8 -NR ₁₂ R ₁₃ , -C _0-8 -C (O) NR ₁₂ R ₁₃ ,- Selected from N (R ₁₂ ) -C (O) R ₁₁ or -N (R ₁₂ ) -C (O) OR ₁₀
R ₁₈ and R ₁₉ are independent halogen, hydroxy group, alkyl group, halo-substituted C _1-8 alkyl group, C _3-8 cycloalkyl group, 3-8 member heterocyclic group, 3-8 member heterocyclic oxygen. Group, 3-8-membered heterocyclic thio group, -C _0-8 -S (O) _r R ₉ , -C _0-8 -OR ₁₀ , -C _0-8 -C (O) OR ₁₀ ,- C _0-8 -C (O) R ₁₁ , -C _0-8 -OC (O) R ₁₁ , -C _0-8 -NR ₁₂ R ₁₃ , -C _0-8 -C (O) NR ₁₂ Selected from R ₁₃ , -N (R ₁₂ ) -C (O) R ₁₁ or -N (R ₁₂ ) -C (O) OR ₁₀
Alternatively, R ₁₈ and R ₁₉ form a cycloalkyl group or a heterocyclic group together with a carbon atom to be directly bonded, and the alkyl group or the heterocyclic group may further form a C _1-8 alkyl group or a C _1-8 . It may be substituted with one or more substituents selected from haloalkyl groups, halogens, hydroxy groups, C _1-8 alkoxy groups and C _1-8 hydroxyalkyl groups.
n is 0-4. )

Further, as a preferred form, in the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, R is selected from hydrogen or fluorine and R ₂ is selected from a cyano group or a thiocyano group.
B ₂ is selected from a methyl group, an ethyl group, a methoxy group, an ethoxy group, a methoxyethyl group, an ethoxymethyl group or an ethoxyethyl group.
R ₁₇ is hydrogen, methyl group, methoxy group, ethoxy group, isopropoxy group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclopropoxy group, cyclobutoxy group, cyclopentoxy group, furanyl group, thienyl group, pyrrolyl group, Selected from an imidazolyl group, a tetrahydrofuranyl group, a tetrahydrothienyl group, a tetrahydropyrrrolyl group, a tetrahydroimidazolyl group, a piperazinyl group or a morpholinyl group,
R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , and R ₈ are independently derived from hydrogen, dehydrogen, fluorine, chlorine, methyl group, ethyl group, isopropyl group, methoxy group, ethoxy group or isopropoxy group, respectively. To be elected.

As the most preferable form, the compound of the formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the following compounds.

Further, as a preferred form, in the compound of the formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, R is selected from hydrogen or fluorine, and R ₂ is selected from a cyano group or a thiocyano group.
B ₂ is selected from a methyl group, an ethyl group, a methoxy group, an ethoxy group, a methoxyethyl group, an ethoxymethyl group or an ethoxyethyl group.
R ₁₇ is a methyl group, a methoxy group, an ethoxy group, an isopropoxy group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a furanyl group, a thienyl group, a pyrrolyl group, an imidazolyl group, a tetrahydrofuranyl group, a tetrahydrothienyl group, a tetrahydropyrrrolyl group. , Tetrahydroimidazolyl group, piperazinyl group or morpholinyl group, selected from
Alternatively, R ₃ and R ₄ , R ₅ and R ₆ , and R ₇ and R ₈ form a cyclopropyl group or a cyclobutyl group together with a directly bonded carbon atom.

As the most preferable form, the compound of the formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the following compounds.

Further, as a preferred form, in the compound of the formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, R is selected from hydrogen or fluorine.
R ₁ is selected from hydrogen, deuterium, furanyl group, thienyl group, pyrrole group, pyrazolyl group, imidazolyl group, azetidinel group, tetrahydrofuranyl group, tetrahydrothienyl group, tetrahydropyrrolyl group, tetrahydropyrazolyl group or tetrahydroimidazolyl group.
In some cases, further, halogen, hydroxy group, alkyl group, halo-substituted C _1-8 alkyl group, C _3-8 cycloalkyl group, 3-8 member heterocyclic group, 3-8 member heterocyclic oxy group, 3-8. Member heterocyclic thio group, -C _0-8 -S (O) _r R ₉ , -C _0-8 -OR ₁₀ , -C _0-8 -C (O) OR ₁₀ , -C _0-8- C (O) R ₁₁ , -C _0-8 -OC (O) R ₁₁ , -C _0-8 -NR ₁₂ R ₁₃ , -C _0-8 -C (O) NR ₁₂ R ₁₃ , -N It may be substituted with one or more substituents selected from (R ₁₂ ) -C (O) R ₁₁ or -N (R ₁₂ ) -C (O) OR ₁₀ .
R ₂ is selected from the cyano group.

As the most preferable form, the compound of the formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the following compounds.

（式中、
Ｚ、Ｙ、Ａ_１、Ｂ_１、Ｘ_１－Ｘ_３、Ｒ_１４－Ｒ_１６又はｎは式（II）化合物に記載のとおりである。） As a preferred embodiment of the present patent, the compound of the formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the compounds of the following formula (IV).

(During the ceremony
Z, Y, A ₁ , B ₁ , X ₁ -X ₃ , R ₁₄ -R ₁₆ or n are as described in Formula (II) Compounds. )

（式中、
環ＣはＣ_３－８シクロアルキル基、３－８員複素環基、Ｃ_５－１０アリール基又は５－１０員ヘテロアリール基から選ばれ、且つ
ｕは０、１、２、３、４又は５であり、
Ｚ、Ａ_１、Ｘ_１－Ｘ_３、Ｒ_１４－Ｒ_１６又はｎは式（II）化合物に記載のとおりである。） As a preferred embodiment of the present patent, the compound of the formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the compounds of the following formula (V).

(During the ceremony
Ring C is selected from C _3-8 cycloalkyl groups, 3-8 membered heterocyclic groups, C _5-10 aryl groups or 5-10 membered heteroaryl groups, and u is 0, 1, 2, 3, 4 or 5 and
Z, A ₁ , X ₁ -X ₃ , R ₁₄ -R ₁₆ or n are as described in Formula (II) Compounds. )

（式中、
Ｘ_１は－（ＣＲ_３Ｒ_４）ｍ_１－、Ｘ_２は－（ＣＲ_５Ｒ_６）ｍ_２－、Ｘ_３は－（ＣＲ_７Ｒ_８）ｍ_３－であり、
Ｒ_３、Ｒ_４、Ｒ_５、Ｒ_６、Ｒ_７、Ｒ_８はそれぞれ独立して水素、重水素、ハロゲン、ヒドロキシ基、カルボキシル基、アミノ基、Ｃ_１－８アルキル基、ハロ置換Ｃ_１－８アルキル基、Ｃ_３－８シクロアルキル基、Ｃ_１－８アルコキシ基又はハロ置換Ｃ_１－８アルコキシ基から選ばれ、前記Ｃ_１－８アルキル基、ハロ置換Ｃ_１－８アルキル基、Ｃ_３－８シクロアルキル基、Ｃ_１－８アルコキシ基及びハロ置換Ｃ_１－８アルコキシ基は場合によって、さらに、ハロゲン、ヒドロキシ基、カルボキシル基、アミノ基、Ｃ_１－８アルキル基、ハロ置換Ｃ_１－８アルキル基、Ｃ_３－８シクロアルキル基、－Ｃ_０－８－Ｓ（Ｏ）_ｒＲ_９、－Ｃ_０－８－Ｏ－Ｒ_１０、－Ｃ_０－８－Ｃ（Ｏ）ＯＲ_１０、－Ｃ_０－８－Ｃ（Ｏ）Ｒ_１１、－Ｃ_０－８－Ｏ－Ｃ（Ｏ）Ｒ_１１、－Ｃ_０－８－ＮＲ_１２Ｒ_１３、－Ｃ_０－８－Ｃ（Ｏ）ＮＲ_１２Ｒ_１３、－Ｎ（Ｒ_１２）－Ｃ（Ｏ）Ｒ_１１及び－Ｎ（Ｒ_１２）－Ｃ（Ｏ）ＯＲ_１０から選ばれる１つ又は複数の置換基によって置換されてもよく、
又は、Ｒ_３とＲ_４、Ｒ_５とＲ_６、Ｒ_７とＲ_８は、直接結合される炭素原子とともにシクロアルキル基又は複素環基を形成し、前記アルキル基又は複素環基は場合によって、さらに、Ｃ_１－８アルキル基、Ｃ_１－８ハロアルキル基、ハロゲン、ヒドロキシ基、Ｃ_１－８アルコキシ基及びＣ_１－８ヒドロキシアルキル基から選ばれる１つ又は複数の置換基によって置換されてもよく、
Ｚ、Ａ_１、ｍ_１－ｍ_３、Ｒ_１７－Ｒ_１９又はｎは式（III）化合物に記載のとおりである。） As a preferred form of the present patent, the compound of the formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the compounds of the following formula (VI).

(During the ceremony
X ₁ is-(CR ₃ R ₄ ) m _1- , X ₂ is-(CR ₅ R ₆ ) m _2- , X ₃ is-(CR ₇ R ₈ ) m _3- .
R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , and R ₈ are independently hydrogen, dear hydrogen, halogen, hydroxy group, carboxyl group, amino group, C _1-8 alkyl group, halo-substituted C _1- It is selected from an ₈ alkyl group, a C _3-8 cycloalkyl group, a C _1-8 alkoxy group or a halo-substituted C _1-8 alkoxy group, and the above-mentioned C _1-8 alkyl group, halo-substituted C _1-8 alkyl group, C _{3 -8} Cycloalkyl group, C _1-8 alkoxy group and halo-substituted C _1-8 alkoxy group may further be halogen, hydroxy group, carboxyl group, amino group, C _1-8 alkyl group, halo-substituted C _{1- 8} Alkyl group, C _3-8 Cycloalkyl group, -C _0-8 -S (O) _r R ₉ , -C _0-8 -OR ₁₀ , -C _0-8 -C (O) OR ₁₀ , -C _0-8 -C (O) R ₁₁ , -C _0-8 -OC (O) R ₁₁ , -C _0-8 -NR ₁₂ R ₁₃ , -C _0-8 -C (O) NR It may be substituted with one or more substituents selected from ₁₂ R ₁₃ , -N (R ₁₂ ) -C (O) R ₁₁ and -N (R ₁₂ ) -C (O) OR ₁₀ .
Alternatively, R ₃ and R ₄ , R ₅ and R ₆ , R ₇ and R ₈ form a cycloalkyl group or heterocyclic group together with the directly bonded carbon atom, and the alkyl group or heterocyclic group may form a cycloalkyl group or a heterocyclic group in some cases. Further, even if it is substituted with one or more substituents selected from a C _1-8 alkyl group, a C _1-8 haloalkyl group, a halogen, a hydroxy group, a C _1-8 alkoxy group and a C _1-8 hydroxyalkyl group. Often,
Z, A ₁ , m ₁ -m ₃ , R ₁₇ -R ₁₉ or n are as described in the compound of formula (III). )

（式中
Ｚ、Ａ_１、Ｂ_１、Ｘ_２、Ｘ_３、Ｒ_１４－Ｒ_１６又はｎは式（II）化合物に記載のとおりである。） As a preferred embodiment of the present patent, the compound of the formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the compounds of the following formula (VI).

(Z, A ₁ , B ₁ , X ₂ , X ₃ , R ₁₄ -R ₁₆ or n in the formula are as described in the compound of formula (II)).

（式中、
Ｚ、Ａ_１、Ｘ_２、Ｘ_３、Ｒ_１７－Ｒ_１９又はｎは式（III）化合物に記載のとおりである。） As a preferred embodiment of the present patent, the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the compound of formula (VIII) below.

(During the ceremony
Z, A ₁ , X ₂ , X ₃ , R ₁₇ -R ₁₉ or n are as described in compound formula (III). )

（式中、
環ＤはＣ_３－８シクロアルキル基、３－８員複素環基、Ｃ_５－１０アリール基又は５－１０員ヘテロアリール基から選ばれ、
Ｒは水素又はフッ素から選ばれ、
Ｒ_２はシアノ基から選ばれ、且つ
ｕは０、１、２、３、４又は５であり、
Ｚ、Ｙ、環Ｃ、Ｘ_１－Ｘ_３、Ｒ_１４は式（II）化合物に記載のとおりである。） As a preferred embodiment of the present patent, the compound of the formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the compounds of the following formula (IX).

(During the ceremony
Ring D is selected from C _3-8 cycloalkyl groups, 3-8 membered heterocyclic groups, C _5-10 aryl groups or 5-10 membered heteroaryl groups.
R is selected from hydrogen or fluorine,
R ₂ is selected from the cyano group and u is 0, 1, 2, 3, 4 or 5.
Z, Y, ring C, X1 _- X3 _, R14 are as described _in formula (II) compound. )

In a preferred embodiment of the present patent, in the compound of formula (I), its steric isomer or a pharmaceutically acceptable salt thereof, R ₁₄ is hydrogen, C _1-8 alkyl group, C _1-8 alkoxy group, halo substituted. C _1-8 alkyl group, C _3-8 cycloalkyl group, 3-8 member heterocyclic group, 3-8 member heterocyclic oxy group, 3-8 member heterocyclic thio group, -C _0-8 -S (O) ) _R R ₉ , -C _0-8 -OR ₁₀ , -C _0-8 -C (O) OR ₁₀ , -C _0-8 -C (O) R ₁₁ , -C _0-8 -O- C (O) R ₁₁ , -C _0-8- NR ₁₂ R ₁₃ , -C _0-8 -C (O) NR ₁₂ R ₁₃ , -N (R ₁₂ ) -C (O) R ₁₁ or -N ( It is characterized in that it is selected from R ₁₂ ) -C (O) OR ₁₀ .

As a preferred embodiment of the present patent, in the compound of formula (I), its steric isomer or a pharmaceutically acceptable salt thereof, R ₁₇ is hydrogen, C _1-8 alkyl group, C _1-8 alkoxy group, halo-substituted. The C _1-8 alkyl group is selected from a C _1-8 alkyl group, a C _3-8 cycloalkyl group, a 3-8 member heterocyclic group, a 3-8 member heterocyclic oxy group, and a 3-8 member heterocyclic thio group. Group, C _1-8 alkoxy group, halo-substituted C _1-8 alkyl group, C _3-8 cycloalkyl group, 3-8 member heterocyclic group, 3-8 member heterocyclic oxy group, 3-8 member heterocyclic thio In some cases, the group may be further substituted with a C _1-8 alkyl group, a C _1-8 alkoxy group, a halo-substituted C _1-8 alkyl group, a C _3-8 cycloalkyl group, a 3-8 member heterocyclic group. It is characterized by being good.

（式中、Ｘ_１、Ｘ_２、Ｘ_３、Ｒ、Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４、Ｒ_５、Ｒ_６、Ｒ_７、Ｒ_８、Ｒ_９、Ｒ_１０、Ｒ_１１、Ｒ_１２、Ｒ_１３、ｒ、Ｚ、ｍ_１、ｍ_２、ｍ_３、Ｙは式（Ｉ）化合物に定義されたとおりであり、Ｐｇはヒドロキシ保護基、好ましくはＣ_１－８アルキル基又はベンジル基である。） A second aspect of the present invention provides a method for producing the compound of formula (I) described above, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and comprises the following steps.

(In the formula, X ₁ , X ₂ , X ₃ , R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , r, Z, m ₁ , m ₂ , m ₃ , and Y are as defined in the compound of formula (I), and Pg is a hydroxy protecting group, preferably a C _1-8 alkyl group or a benzyl group. be.)

A third aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

A fourth aspect of the present invention provides an application of the above-mentioned compound (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the production of a FGFR4 inhibitor drug.

A fifth aspect of the present invention provides an application of the above-mentioned compound (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the manufacture of a therapeutic agent for cancer.

Preferably, the cancer is liver cancer, gastric cancer, prostate cancer, skin cancer, ovarian cancer, lung cancer, breast cancer, colon cancer, glioma or rhizome myoma.

The present invention further relates to a method for treating / preventing and / or treating / preventing a disease related to an FGFR4 inhibitor in a therapeutically effective amount of a compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable thereof. Includes the step of administering to a patient a salt, or a pharmaceutical composition containing the same.

Another aspect of the invention relates to a method of treating cancer, wherein the method provides a patient with a therapeutically effective amount of a compound represented by the general formula (I) of the present invention, a stereoisomer thereof or a pharmaceutically acceptable salt thereof. Includes the step of administration. The method has outstanding therapeutic effect and few side effects, and the cancer is selected from liver cancer, gastric cancer, prostate cancer, skin cancer, ovarian cancer, lung cancer, breast cancer, colon cancer, glioma or rhizome myoma. May be.

Specifically, unless otherwise specified, the following terms used in the present specification and claims have the following meanings.

The "C _1-8 alkyl group" means a linear alkyl group having 1-8 carbon atoms and a branched alkyl group, and the alkyl group is a saturated aliphatic hydrocarbon group, for example, a methyl group or an ethyl group. , N-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, s-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2, 2-Dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1 -Dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group Group, 2,3-dimethylbutyl group, n-heptyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 5-methylhexyl group, 2,3-dimethylpentyl group, 2,4 -Dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, n-octyl group, 2,3-dimethylhexyl group, 2,4- Dimethylhexyl group, 2,5-dimethylhexyl group, 2,2-dimethylhexyl group, 3,3-dimethylhexyl group, 4,4-dimethylhexyl group, 2-ethylhexyl group, 3-ethylhexyl group, 4-ethylhexyl group , 2-Methyl-2-ethylpentyl group, 2-methyl group-3-ethylpentyl group or various branched isomers thereof, and the like, preferably methyl group, ethyl group, propyl group and the like.

The "cycloalkyl group" means, in some cases, a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, and the "C _3-8 cycloalkyl group" has 3-8 carbon atoms. Means a cycloalkyl group, for example
Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclo戊alkenyl group, cyclohexyl group, cyclohexene group, cyclonedialkenyl group, cycloheptyl group, cycloheptatrienyl. It contains a group, a cyclooctyl group and the like, and is preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and more preferably a cyclopropyl group.

Polycyclic cycloalkyl groups include cycloalkyl groups of spiro, fused and crosslinked rings. A "spiroalkyl group" is a polycyclic group in which monocycles share one carbon atom (called a spiro atom), and may contain one or more double bonds, but any ring may contain one or more double bonds. Does not have a fully conjugated π electron system. Spiroalkyl groups are divided into monospiroalkyl groups, bisspiroalkyl groups or polyspiroalkyl groups according to the number of spiroatoms shared by the rings, and non-limiting examples of spiroalkyl groups include:

"Fused cycloalkyl group" means a total carbon polycyclic group in which each ring in the system and another ring in the system share a pair of adjacent carbon atoms, with one or more rings being one or more. It may contain multiple double bonds, but none of the rings has a fully conjugated π-electron system. It is divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups according to the number of constituent rings, and non-limiting examples of condensed cycloalkyl groups include:

The "bridged cycloalkyl group" means an all-carbon polycyclic group that shares two carbon atoms to which any two rings do not directly bond, although it may contain one or more double bonds. , Neither ring has a fully conjugated π-electron system. It is divided into bicyclic, tricyclic, tetracyclic or polycyclic crosslinked cycloalkyl groups according to the number of constituent rings, and non-limiting examples of crosslinked cycloalkyl groups include:

The cycloalkyl ring may be fused to a ring of an aryl group, a heteroaryl group or a heterocyclic alkyl group, wherein the ring bonded to the parent structure is a cycloalkyl group, and a non-limiting example is indanyl. Includes groups, tetrahydronaphthyl groups, benzocycloheptanyl groups and the like.

The cycloalkyl group may or may not be substituted, and when substituted, the substituents are preferably independently halogen, hydroxy, mercapto, cyano, nitro, oxo groups. , Azide group, C _1-8 alkyl group, C _2-8 alkenyl group, C _2-8 alkynyl group, C _3-8 cycloalkyl group, 3-8 member heterocyclic group, 3-8 member heterocyclic oxy group, 3-8-membered heterocyclic thio group, C _5-10 aryl group, C _5-10 aryloxy group, C _5-10 arylthio group, 5-10 member heteroaryl group, 5-10 member heteroaryloxy group, 5- 10-membered heteroarylthio group, -C _0-8 -S (O) _r R ₉ , -C _0-8 -OR ₁₀ , -C _0-8 -C (O) OR ₁₀ , -C _0-8 -C (O) R ₁₁ , -C _0-8 -OC (O) R ₁₁ , -C _0-8 -NR ₁₂ R ₁₃ , -C _0-8 -C (O) NR ₁₂ R ₁₃ ,- Substituted by one or more substituents selected from N (R ₁₂ ) -C (O) R ₁₁ or -N (R ₁₂ ) -C (O) OR ₁₀ .

By "heterocyclic group" is optionally meant a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, where one or more ring atoms are nitrogen, oxygen or S (O) _r ( Here, r is a heteroatom selected from (which is an integer of 0, 1, 2), but does not include the ring portion of —O—, —OS— or —SS— and the remaining ring. The atom is carbon. The "5-10-membered heterocyclic group" means a cyclo group containing 5-10 ring atoms, and the "3-8-membered heterocyclic group" means a cyclo group containing 3-8 ring atoms. ..

Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, oxazolidine, tetrahydrothiophene, oxoazepan, homopiperazinyl group and the like, preferably oxoazepan, pyrrolidinyl group, etc. It is a morphinyl group, an oxazolidinone, an oxazolidinethione, and a piperazinyl group.

Polycyclic heterocyclic groups include heterocyclic groups of spiro, fused and crosslinked rings. "Spiro heterocyclic group" means a polycyclic heterocyclic group in which monocycles share one atom (called a spiro atom), and one or more ring atoms are nitrogen, oxygen or S (O). ) _R (where r is a 0, 1, 2 integer) is a heteroatom, the remaining ring atom is carbon. They may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. Spiroalkyl groups are classified into monospiro heterocyclic groups, bisspiro heterocyclic groups or polyspiro heterocyclic groups according to the number of spiro atoms shared by the rings. Non-limiting examples of spiroalkyl groups include:

"Fused heterocyclic group" means a polycyclic heterocyclic group in which each ring in the system and another ring in the system share a pair of adjacent atoms, and one or more rings are one or more. It may contain a double bond of, but none of the rings has a fully conjugated π-electron system and one or more ring atoms can be nitrogen, oxygen or S (O) _r (where r is a heteroatom selected from (0, 1, 2 integers), and the remaining ring atom is carbon. It is divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups according to the number of constituent rings, and non-limiting examples of fused heterocyclic groups include:

By "bridged heterocyclic group" is meant a polycyclic heterocyclic group that shares two atoms to which either two rings are not directly bonded, although it may contain one or more double bonds. , Neither ring has a fully conjugated π-electron system, and one or more ring atoms are nitrogen, oxygen or S (O) _r (where r is 0, 1, 2 integers). It is a heteroatom selected from, and the remaining ring atom is carbon. It is divided into bicyclic, tricyclic, tetracyclic or polycyclic crosslinked cycloalkyl groups according to the number of constituent rings, and non-limiting examples of crosslinked cycloalkyl groups include:

The heterocyclic base ring can be fused to an aryl group, a heteroaryl group or a cycloalkyl ring, and the ring bonded to the parent structure is a heterocyclic group, and examples thereof include the following.

The heterocyclic group may or may not be substituted, and when substituted, the substituents are preferably independently halogen, hydroxy, mercapto, cyano, nitro, oxo. Group, azide group, C _1-8 alkyl group, C _2-8 alkenyl group, C _2-8 alkynyl group, C _3-8 cycloalkyl group, 3-8 member heterocyclic group, 3-8 member heterocyclic oxy group , 3-8-membered heterocyclic thio group, C _5-10 aryl group, C _5-10 aryloxy group, C _5-10 arylthio group, 5-10 member heteroaryl group, 5-10 member heteroaryloxy group, 5 -10-membered heteroarylthio group, -C _0-8 -S (O) _r R ₉ , -C _0-8 -OR ₁₀ , -C _0-8 -C (O) OR ₁₀ , -C _{0- 8} -C (O) R ₁₁ , -C _0-8 -OC (O) R ₁₁ , -C _0-8 -NR ₁₂ R ₁₃ , -C _0-8 -C (O) NR ₁₂ R ₁₃ , Substituted by one or more substituents selected from -N (R ₁₂ ) -C (O) R ₁₁ or -N (R ₁₂ ) -C (O) OR ₁₀ .

An "aryl group" is a total carbon monocyclic or fused polycyclic (that is, a ring that shares adjacent carbon atom pairs) group, a polycyclic type that has a conjugated π-electron system (that is, a ring that has adjacent carbon atom pairs). The "C _5-10 aryl group" means a total carbon aryl group having 5-10 carbon atoms, and the "5-10 member aryl group" means a total carbon aryl group having 5-10 carbon atoms, for example. It is a phenyl group and a naphthyl group, preferably a phenyl group. The aryl ring can be condensed into a heteroaryl group, a heterocyclic group or a cycloalkyl ring, and the ring bonded to the parent structure is an aryl ring, and non-limiting examples include the following.

The aryl group may or may not be substituted, and when substituted, the substituent is preferably independently a halogen, a hydroxy group, a mercapto group, a cyano group, a nitro group, an azide group. , C _1-8 alkyl group, C _2-8 alkenyl group, C _2-8 alkynyl group, C _3-8 cycloalkyl group, 3-8 member heterocyclic group, 3-8 member heterocyclic oxy group, 3-8 Membered heterocyclic thio group, C _5-10 aryl group, C _5-10 aryloxy group, C _5-10 aryl thio group, 5-10 member heteroaryl group, 5-10 member heteroaryloxy group, 5-10 member hetero Arylthio groups, -C _0-8 -S (O) _r R ₉ , -C _0-8 -OR ₁₀ , -C _0-8 -C (O) OR ₁₀ , -C _0-8 -C ( O) R ₁₁ , -C _0-8 -OC (O) R ₁₁ , -C _0-8 -NR ₁₂ R ₁₃ , -C _0-8 -C (O) NR ₁₂ R ₁₃ , -N (R) ₁₂ ) Substituted by one or more substituents selected from -C (O) R ₁₁ or -N (R ₁₂ ) -C (O) OR ₁₀ .

"Heteroaryl group" means a heteroaromatic system containing 1-4 heteroatoms, the heteroatoms being nitrogen, oxygen and S (O) r (where r is 0, 1, 2 integers. A 5-7-membered heteroaryl group is a heteroaromatic system containing 5-7 ring atoms, and a 5-10-membered heteroaryl group is a 5-10 ring. It means a heteroaromatic system containing an atom, and examples thereof include a furanyl group, a thienyl group, a pyridyl group, a pyrrolyl group, an N-alkylpyrrolyl group, a pyrimidinyl group, a pyrazinyl group, an imidazolyl group, a tetrazolyl group, and the like. It is a pyridyl group. The heteroaryl ring can be fused to an aryl group, a heterocyclic group or a cycloalkyl ring, the ring bonded to the parent structure is a heteroaryl ring, and non-limiting examples include:

Heteroaryl groups may or may not be substituted, as the case may be, and when substituted, the substituents are preferably independently halogen, hydroxy groups, mercapto groups, cyano groups, nitro groups. , Azide group, C _1-8 alkyl group, C _2-8 alkenyl group, C _2-8 alkynyl group, C _3-8 cycloalkyl group, 3-8 member heterocyclic group, 3-8 member heterocyclic oxy group, 3-8-membered heterocyclic thio group, C _5-10 aryl group, C _5-10 aryloxy group, C _5-10 arylthio group, 5-10 member heteroaryl group, 5-10 member heteroaryloxy group, 5- 10-membered heteroarylthio group, -C _0-8 -S (O) _r R ₉ , -C _0-8 -OR ₁₀ , -C _0-8 -C (O) OR ₁₀ , -C _0-8 -C (O) R ₁₁ , -C _0-8 -OC (O) R ₁₁ , -C _0-8 -NR ₁₂ R ₁₃ , -C _0-8 -C (O) NR ₁₂ R ₁₃ ,- Substituted by one or more substituents selected from N (R ₁₂ ) -C (O) R ₁₁ or -N (R ₁₂ ) -C (O) OR ₁₀ .

The "alkenyl group" is an alkyl group defined as described above, which is composed of at least two carbon atoms and at least one carbon-carbon double bond, and the C _2-8 alkenyl group has 2-8 carbon atoms. Means a linear or branched alkenyl group of. For example, an ethynyl group, a 1-propenyl group, a 2-propenyl group, a 1-, 2- or 3-butynyl group and the like can be mentioned.

The alkenyl group may or may not be substituted, and when substituted, the substituents are preferably independently halogen, hydroxy, mercapto, cyano, nitro, azide groups, C _1-8 alkyl group, C _2-8 alkenyl group, C _2-8 alkynyl group, C _3-8 cycloalkyl group, 3-8 member heterocyclic group, 3-8 member heterocyclic oxy group, 3-8 member Heterocyclic thio group, C _5-10 aryl group, C _5-10 aryloxy group, C _5-10 aryl thio group, 5-10 member heteroaryl group, 5-10 member heteroaryloxy group, 5-10 member heteroally Lucio group, -C _0-8 -S (O) _r R ₉ , -C _0-8 -OR ₁₀ , -C _0-8 -C (O) OR ₁₀ , -C _0-8 -C (O) ) R ₁₁ , -C _0-8 -OC (O) R ₁₁ , -C _0-8 -NR ₁₂ R ₁₃ , -C _0-8 -C (O) NR ₁₂ R ₁₃ , -N (R ₁₂ ) ) -C (O) R ₁₁ or -N (R ₁₂ ) -C (O) OR ₁₀ is substituted by one or more substituents selected.

The "alkynyl group" is an alkyl group defined as described above, which is composed of at least two carbon atoms and at least one carbon-carbon triple bond, and the C _2-8 alkynyl group has 2-8 carbon atoms. It means a linear or branched alkynyl group. For example, an aceethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-, 2- or 3-butynyl group and the like can be mentioned.

The alkynyl group may or may not be substituted, and when substituted, the substituents are preferably independently halogen, hydroxy group, mercapto group, cyano group, nitro group, azide group, C _1-8 alkyl group, C _2-8 alkenyl group, C _2-8 alkynyl group, C _3-8 cycloalkyl group, 3-8 member heterocyclic group, 3-8 member heterocyclic oxy group, 3-8 member Heterocyclic thio group, C _5-10 aryl group, C _5-10 aryloxy group, C _5-10 aryl thio group, 5-10 member heteroaryl group, 5-10 member heteroaryloxy group, 5-10 member heteroally Lucio group, -C _0-8 -S (O) _r R ₉ , -C _0-8 -OR ₁₀ , -C _0-8 -C (O) OR ₁₀ , -C _0-8 -C (O) ) R ₁₁ , -C _0-8 -OC (O) R ₁₁ , -C _0-8 -NR ₁₂ R ₁₃ , -C _0-8 -C (O) NR ₁₂ R ₁₃ , -N (R ₁₂ ) ) -C (O) R ₁₁ or -N (R ₁₂ ) -C (O) OR ₁₀ is substituted by one or more substituents selected.

The "alkoxy group" is, in some cases, —O— (alkyl group), and the definition of the alkyl group is as described above. The “C _1-8 alkoxy group” means a cycloalkyloxy group having 1 to 8 carbon atoms, and non-limiting examples include a methoxy group, an ethoxy group, a propoxy group, a butoxy group and the like, preferably. It is a methoxy group.

The alkoxy group may or may not be substituted, and when substituted, the substituent is preferably an independently halogen, hydroxy group, mercapto group, cyano group, nitro group, azide group, C _1-8 alkyl group, C _2-8 alkenyl group, C _2-8 alkynyl group, C _3-8 cycloalkyl group, 3-8 member heterocyclic group, 3-8 member heterocyclic oxy group, 3-8 member Heterocyclic thio group, C _5-10 aryl group, C _5-10 aryloxy group, C _5-10 aryl thio group, 5-10 member heteroaryl group, 5-10 member heteroaryloxy group, 5-10 member heteroally Lucio group, -C _0-8 -S (O) _r R ₉ , -C _0-8 -OR ₁₀ , -C _0-8 -C (O) OR ₁₀ , -C _0-8 -C (O) ) R ₁₁ , -C _0-8 -OC (O) R ₁₁ , -C _0-8 -NR ₁₂ R ₁₃ , -C _0-8 -C (O) NR ₁₂ R ₁₃ , -N (R ₁₂ ) ) -C (O) R ₁₁ or -N (R ₁₂ ) -C (O) OR ₁₀ is substituted by one or more substituents selected.

By "cycloalkoxy group", in some cases, it means —O— (unsubstituted cycloalkyl group), and the definition of cycloalkyl group is as described above. "C _3-8 cycloalkoxy group" means a cyclocycloalkyloxy group having 3-8 carbon atoms, and non-limiting examples include a cyclopropoxy group, a cyclobutoxy group, a cyclopentoxy group, and a cyclohexyloxy group. Including groups and the like.

The alkoxy group may or may not be substituted, and when substituted, the substituent is preferably an independently halogen, hydroxy group, mercapto group, cyano group, nitro group, azide group, C _1-8 alkyl group, C _2-8 alkenyl group, C _2-8 alkynyl group, C _3-8 cycloalkyl group, 3-8 member heterocyclic group, 3-8 member heterocyclic oxy group, 3-8 member Heterocyclic thio group, C _5-10 aryl group, C _5-10 aryloxy group, C _5-10 aryl thio group, 5-10 member heteroaryl group, 5-10 member heteroaryloxy group, 5-10 member heteroally Lucio group, -C _0-8 -S (O) _r R ₉ , -C _0-8 -OR ₁₀ , -C _0-8 -C (O) OR ₁₀ , -C _0-8 -C (O) ) R ₁₁ , -C _0-8 -OC (O) R ₁₁ , -C _0-8 -NR ₁₂ R ₁₃ , -C _0-8 -C (O) NR ₁₂ R ₁₃ , -N (R ₁₂ ) ) -C (O) R ₁₁ or -N (R ₁₂ ) -C (O) OR ₁₀ is substituted by one or more substituents selected.

The "halo-substituted C _1-8 alkyl group" means, in some cases, an alkyl group having 1-8 carbon atoms in which hydrogen in the alkyl group may be substituted with fluorine, chlorine, bromine and iodine atoms, for example, difluoromethyl. Examples thereof include a group, a dichloromethyl group, a dibromomethyl group, a trifluoromethyl group, a trichloromethyl group, and a tribromomethyl group.

The "halo-substituted C _1-8 alkoxy group" means an alkoxy group having 1 to 8 carbon atoms in which hydrogen in the alkyl group may be substituted with fluorine, chlorine, bromine, or iodine atoms. For example, a difluoromethoxy group, a dichloromethoxy group, a dibromomethoxy group, a trifluoromethoxy group, a trichloromethoxy group, a tribromomethoxy group and the like can be mentioned.

"Halogen" is fluorine, chlorine, bromine or iodine.
"Fluorine" and "chlorine" are tetrahydrofuran.
Tetrahydrofuran or ethyl acetate.
"Ethyl acetate" is methanol.
"DMF" is N, N-dimethylformamide.
"Methylformamide" is diisopropylethylamine.
"TFA" is trifluoroacetic acid.
"MeCN" is acetonitrile.
"DMA" is N, N-dimethylacetamide.
"Et ₂ O" is ether.
"DCE" is 1,2-dichloroethane.
"DIPEA" is N, N-diisopropylethylamine.
"NBS" is N-bromosuccinimide.
"NIS" is N-iodosuccinimide.
"Cbz-Cl" is benzyl chloroformate.
“Pd ₂ (dba) ₃ ” is tris (dibenzylideneacetone) dipalladium.
"Dppf" is 1,1'-bisdiphenylphosphinoferrocene.
"HATU" is O- (7-azabenzotriazole-1-yl) -N, N, N', N'-tetramethyluronium-hexafluorophosphate.
"KHMDS" is potassium hexamethyldisilazide.
"LiHMDS" is bis (trimethylsilyl) amidolithium.
"MeLi" is methyllithium.
"N-BuLi" is n-butyllithium.
"NaBH (OAc) ₃ " is sodium triacetoxyborohydride.
The "stereoisomer" includes three types: geometric isomers (cis and trans isomers), optical isomers, and conformers.
"X is chosen from A, B or C", "X is chosen from A, B and C", "X is A, B or C", "X is A, B and C", etc. The various terms of have the same meaning, that is, X may be any one or more of A, B, and C.

Any of the hydrogen atoms of the present invention may be substituted with a heavy hydrogen atom thereof, and any hydrogen atom may be substituted with a heavy hydrogen atom in the example compound of the present invention.

"In some cases" or "may be" means that an event or environment described below can occur, but does not need to occur, and the description is when or occurs when the event or environment occurs. Including the case of not doing so. For example, "in some cases, a heterocyclic group substituted with an alkyl group" means that an alkyl group may exist, but it does not always exist, and the description thereof is that the heterocyclic group is substituted with an alkyl group and the complex is complex. This includes the case where the ring group is not substituted with an alkyl group.

By "substituted" is meant that one or more hydrogen atoms in a group have been independently substituted with a corresponding number of substituents. Of course, the substituents are only at possible chemical positions, and one of ordinary skill in the art can determine possible or impossible substitutions (by experiment or theory) without considerable effort. For example, an amino group or a hydroxy group having free hydrogen may become unstable when bonded to a carbon atom having an unsaturated bond (for example, an olefin).

A "pharmaceutical composition" is a mixture of one or more compounds described herein or a physiologically / pharmaceutically acceptable salt or prodrug thereof and other chemical components, as well as physiological / pharmaceutical. Means one containing other components such as a pharmaceutically acceptable carrier or excipient. The purpose of the pharmaceutical composition is to facilitate administration into the body, facilitating the absorption of the active ingredient, thereby exerting biological activity.

Hereinafter, the present invention will be described in detail and completely with reference to Examples, but the present invention is not limited to this, and is not limited to the contents of Examples.

The compound structure of the present invention is determined by nuclear magnetic resonance (NMR) and / and liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (δ) is shown as a unit of one million (ppm). A Bruker AVANCE-400 nuclear magnetic resonance apparatus was used for NMR measurement, and deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated methanol (CD ₃ OD) and deuterated chloroform (CDCl ₃ ) were used as measurement solvents. Is used, and tetramethylsilane (TMS) is used as an internal standard.

Liquid Chromatography Mass Spectrometry The Agilent 1200 Infinity Series Mass Spectrometer is used for LC-MS measurements. Agilent 1200DAD High Performance Liquid Chromatography (Sunfire C18 150 x 4.6 mm Chromatography Column) and Waters 2695-2996 High Performance Liquid Chromatography (Gimili C18 150 x 4.6 mm Chromatography Column) are used for HPLC measurements.

HSGF254 or Qingdao GF254 silica gel plate manufactured by Yukidai Huanghai is used as the thin layer chromatography silica gel plate, and the standard used for TLC is 0.15 mm to 0.20 mm, which is used when separating and purifying the product by thin layer chromatography. The standard to be applied is 0.4 mm to 0.5 mm. In column chromatography, silica gel of 200 to 300 mesh manufactured by Yantai Yellow Sea is generally used as a carrier.

The starting material in the examples of the present invention may be known and available as a commercially available product, or may be synthesized according to a method known in the art.

Unless otherwise specified, all reactions of the present invention are carried out in a dry nitrogen or argon atmosphere with continuous magnetic agitation, the solvent is a dry solvent and the reaction temperature is ° C.

Manufacture of intermediates

ステップ１：４－フルオロ－５－ヨードピリジン－２－アミンの製造

４－フルオロピリジン－２－アミン（９ｇ、８０ｍｍｏｌ）、ＮＩＳ（１９．８ｇ、８８ｍｍｏｌ）、ＴＦＡ（３．６５ｇ、３２ｍｍｏｌ）をＭｅＣＮ（２９０ｍＬ）に混合して、室温で一晩反応させた。酢酸エチル（３００ｍＬ）で希釈して、飽和Ｎａ_２ＳＯ_３水溶液（１５０ｍＬ×２）で洗浄して、有機相を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させて濃縮させ、表題化合物である４－フルオロ－５－ヨードピリジン－２－アミン（１５．８ｇ、８３％）を得た。
ＭＳ ｍ／ｚ （ＥＳＩ）： ２３８．９ ［Ｍ＋Ｈ］^＋．
ステップ２：６－アミノ－４－フルオロニコチノニトリルの製造

４－フルオロ－５－ヨードピリジン－２－アミン（１５．８ｇ、６６．４ｍｍｏｌ）、Ｚｎ（ＣＮ）_２（８．２ｇ、６９．８ｍｍｏｌ）、Ｚｎ（０．８７ｇ、１３．３ｍｍｏｌ）をＤＭＡ（５５ｍＬ）に混合して、窒素雰囲気下でＰｄ_２（ｄｂａ）_３（２．４ｇ、２．６２ｍｍｏｌ）とｄｐｐｆ（７．４ｇ、１３．３５ｍｍｏｌ）を加え、窒素で３回置換し、窒素雰囲気下で１１０℃に昇温して３ｈ反応させた。反応液を室温に冷却させて、酢酸エチル（１００ｍＬ）で希釈し、飽和ＮａＨＣＯ_３水溶液（２００ｍｌ）を加えて分液し、水相を酢酸エチル（１５０ｍＬ×３）で抽出して、有機相を合併し、飽和食塩水で洗浄して、無水硫酸ナトリウムで乾燥させて濃縮させ、表題化合物である６－アミノ－４－フルオロニコチノニトリル（７．３ｇ、８０％）を得た。
ＭＳ ｍ／ｚ （ＥＳＩ）： １３８．１［Ｍ＋Ｈ］^＋． Preparation of Intermediate 1: 6-Amino-4-fluoronicotinonitrile

Step 1: Preparation of 4-fluoro-5-iodopyridine-2-amine

4-Fluoropyridin-2-amine (9 g, 80 mmol), NIS (19.8 g, 88 mmol) and TFA (3.65 g, 32 mmol) were mixed with MeCN (290 mL) and reacted overnight at room temperature. Dilute with ethyl acetate (300 mL), wash with saturated aqueous Na ₂ SO ₃ solution (150 mL x 2), wash the organic phase with saturated brine, dry over anhydrous sodium sulfate and concentrate to give the title compound. 4-Fluoro-5-iodopyridine-2-amine (15.8 g, 83%) was obtained.
MS m / z (ESI): 238.9 [M + H] ⁺ .
Step 2: Production of 6-amino-4-fluoronicotinonitrile

4-Fluoro-5-iodopyridine-2-amine (15.8 g, 66.4 mmol), Zn (CN) ₂ (8.2 g, 69.8 mmol), Zn (0.87 g, 13.3 mmol) was added to DMA ( 55 mL), add Pd ₂ (dba) ₃ (2.4 g, 2.62 mmol) and dppf (7.4 g, 13.35 mmol) under a nitrogen atmosphere, replace with nitrogen three times, and under a nitrogen atmosphere. The temperature was raised to 110 ° C. and the reaction was carried out for 3 hours. The reaction mixture is cooled to room temperature, diluted with ethyl acetate (100 mL), saturated aqueous NaHCO ₃ solution (200 ml) is added to separate the solutions, and the aqueous phase is extracted with ethyl acetate (150 mL × 3) to obtain an organic phase. The mixture was washed with saturated aqueous saline solution, dried over anhydrous sodium sulfate and concentrated to give the title compound 6-amino-4-fluoronicotinonitrile (7.3 g, 80%).
MS m / z (ESI): 138.1 [M + H] ⁺ .

６－アミノ－４－フルオロニコチノニトリル（４．１１ｇ、３０ｍｍｏｌ）、２－メトキシエタン－１－アミン（４．５ｇ、６０ｍｍｏｌ）、ＤＩＰＥＡ（１．１６ｇ、９０ｍｍｏｌ）をＤＭＦ（１２０ｍＬ）に混合して、６０℃で一晩反応させた。反応液を濃縮させて、残留物をジクロロメタン（１００ｍＬ）に溶解して、飽和ＮａＨＣＯ_３（１００ｍＬ）水溶液を加えて分液し、有機相を飽和ＮａＣｌ水溶液（５０ｍＬ×２）で洗浄して、有機相を無水硫酸ナトリウムで乾燥させて濃縮させ、カラムクロマトグラフィーをして、表題化合物である６－アミノ－４－（（２－メトキシエチル）アミノ）ニコチノニトリル（３．８４ｇ、６７％）を得た。
１Ｈ ＮＭＲ （４００ ＭＨｚ, ＤＭＳＯ） δ ７．９３ （ｓ, １Ｈ）, ６．３９ （ｓ, ２Ｈ）, ６．１４ （ｔ, Ｊ ＝ ５．６ Ｈｚ, １Ｈ）, ５．６２ （ｓ, １Ｈ）, ３．４７ （ｔ, Ｊ ＝ ６．０ Ｈｚ, ２Ｈ）, ３．２９－３．２２ （ｍ, ５Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： １９３．１［Ｍ＋Ｈ］^＋． Preparation of Intermediate 2: 6-Amino-4-((2-Methoxyethyl) Amino) Nicotinonitrile

6-Amino-4-fluoronicotinonitrile (4.11 g, 30 mmol), 2-methoxyethane-1-amine (4.5 g, 60 mmol) and DIPEA (1.16 g, 90 mmol) are mixed with DMF (120 mL). The reaction was carried out at 60 ° C. overnight. The reaction mixture is concentrated, the residue is dissolved in dichloromethane (100 mL), saturated aqueous NaCl ₃ (100 mL) solution is added to separate the solutions, and the organic phase is washed with saturated aqueous NaCl solution (50 mL × 2) to make the organic phase organic. The phase was dried over anhydrous sodium sulfate, concentrated and column chromatographed to give the title compound 6-amino-4-((2-methoxyethyl) amino) nicotinonitrile (3.84 g, 67%). Obtained.
1H NMR (400 MHz, DMSO) δ 7.93 (s, 1H), 6.39 (s, 2H), 6.14 (t, J = 5.6 Hz, 1H), 5.62 (s, 1H) ), 3.47 (t, J = 6.0 Hz, 2H), 3.29-3.22 (m, 5H);
MS m / z (ESI): 193.1 [M + H] ⁺ .

６－アミノ－４－（（２－（ピロリジン－１－イル）エチル）アミノ）ニコチノニトリルの製造方法は中間体２を参照すればよい。
ＭＳ ｍ／ｚ （ＥＳＩ）： ２３２．１［Ｍ＋Ｈ］^＋． Preparation of Intermediate 3: 6-Amino-4-((2- (Pyrrolidine-1-yl) Ethyl) Amino) Nicotinonitrile

For the method for producing 6-amino-4-((2- (pyrrolidin-1-yl) ethyl) amino) nicotinonitrile, refer to Intermediate 2.
MS m / z (ESI): 232.1 [M + H] ⁺ .

６－アミノ－４－（（２－（シクロペントキシ）エチル）アミノ）ニコチノニトリルの製造方法は中間体２を参照すればよい
ＭＳ ｍ／ｚ （ＥＳＩ）： ２４７．１［Ｍ＋Ｈ］^＋． Preparation of Intermediate 4: 6-Amino-4-((2- (cyclopentoxy) Ethyl) Amino) Nicotinonitrile

For the method for producing 6-amino-4-((2- (cyclopentoxy) ethyl) amino) nicotinonitrile, refer to Intermediate 2. MS m / z (ESI): 247.1 [M + H] ⁺ .

６－アミノ－４－（３－メトキシピロリジン－１－イル）ニコチノニトリルの製造方法は中間体２を参照すればよい。
ＭＳ ｍ／ｚ （ＥＳＩ）： ２１９．１［Ｍ＋Ｈ］^＋． Preparation of Intermediate 5: 6-Amino-4- (3-Methoxypyrrolidin-1-yl) Nicotinonitrile

For the method for producing 6-amino-4- (3-methoxypyrrolidine-1-yl) nicotinonitrile, refer to Intermediate 2.
MS m / z (ESI): 219.1 [M + H] ⁺ .

ステップ１：ベンジル（（トランス）－２－ヒドロキシシクロペンチル）カルバメートの製造

（トランス）－２－アミノシクロペンタン－１－オール（１ｇ、１０ｍｍｏｌ）、Ｎａ_２ＣＯ_３（３．４ｇ、３０ｍｍｏｌ）を水（２０ｍＬ）に混合して、０℃で、反応液にＣｂｚ－Ｃｌ（３．４ｇ、２０ｍｍｏｌ）を滴下し、室温に自然昇温して一晩反応させた。水（３０ｍＬ）で希釈して、酢酸エチル（５０ｍＬ×２）で抽出し、有機相を飽和食塩水で洗浄して、無水硫酸ナトリウムで乾燥させて濃縮させ、カラムクロマトグラフィーをして、表題化合物であるベンジル（（トランス）－２－ヒドロキシシクロペンチル）カルバメート（１．３２ｇ、５６％）を得た。
ＭＳ ｍ／ｚ （ＥＳＩ）： ２３６．２ ［Ｍ＋Ｈ］^＋．
ステップ２：ベンジル（（トランス）－２－メトキシシクロペンチル）カルバメートの製造

ベンジル（（トランス）－２－ヒドロキシシクロペンチル）カルバメート（４７０ｍｇ、２ｍｍｏｌ）をＴＨＦ（２０ｍＬ）に溶解して、０℃で反応液にＮａＨ（９６ｍｇ、２．４ｍｍｏｌ）を加え、３０ｍｉｎ反応させて、ＣＨ_３Ｉ（３１２ｍｇ、３０ｍｍｏｌ）を滴下し、室温に自然昇温して一晩反応させた。飽和ＮＨ_４Ｃｌ水溶液（５０ｍＬ）を加えて、酢酸エチル（５０ｍＬ×２）で抽出し、有機相を飽和食塩水で洗浄して、無水硫酸ナトリウムで乾燥させて濃縮させ、カラムクロマトグラフィーをして、表題化合物であるベンジル（（トランス）－２－メトキシシクロペンチル）カルバメート（３００ｍｇ、６０％）を得た。
ＭＳ ｍ／ｚ （ＥＳＩ）： ２５０．１［Ｍ＋Ｈ］^＋．
ステップ３：（トランス）－２－メトキシシクロペンタン－１－アミンの製造

ベンジル（（トランス）－２－メトキシシクロペンチル）カルバメート（３００ｍｇ、１．２ｍｍｏｌ）をメタノール（３０ｍＬ）に溶解して、１０％Ｐｄ／Ｃ（６０ｍｇ）を加え、Ｈ_２雰囲気において、室温で２ｈ反応させた。濾過して濃縮させ、表題化合物である（トランス）－２－メトキシシクロペンタン－１－アミン（７０ｍｇ、５０％）を得た。
ＭＳ ｍ／ｚ （ＥＳＩ）： １１６．２ ［Ｍ＋Ｈ］^＋．
ステップ４：６－アミノ－４－（（（トランス）－２－メトキシシクロペンチル）アミノ）ニコチノニトリルの製造

６－アミノ－４－（（（トランス）－２－メトキシシクロペンチル）アミノ）ニコチノニトリルの製造方法は中間体２を参照すればよい。
ＭＳ ｍ／ｚ （ＥＳＩ）： ２３３．２ ［Ｍ＋Ｈ］^＋． Preparation of Intermediate 6: 6-Amino-4-(((Trans) -2-Methoxycyclopentyl) Amino) Nicotinonitrile

Step 1: Preparation of benzyl ((trans) -2-hydroxycyclopentyl) carbamate

(Trans) -2-aminocyclopentane-1-ol (1 g, 10 mmol) and Na ₂ CO ₃ (3.4 g, 30 mmol) are mixed with water (20 mL), and Cbz-Cl is added to the reaction solution at 0 ° C. (3.4 g, 20 mmol) was added dropwise, the temperature was naturally raised to room temperature, and the reaction was allowed to proceed overnight. Dilute with water (30 mL), extract with ethyl acetate (50 mL x 2), wash the organic phase with saturated saline, dry over anhydrous sodium sulfate, concentrate, perform column chromatography and perform the title compound. Benzyl ((trans) -2-hydroxycyclopentyl) carbamate (1.32 g, 56%) was obtained.
MS m / z (ESI): 236.2 [M + H] ⁺ .
Step 2: Preparation of benzyl ((trans) -2-methoxycyclopentyl) carbamate

Benzyl ((trans) -2-hydroxycyclopentyl) carbamate (470 mg, 2 mmol) is dissolved in THF (20 mL), NaH (96 mg, 2.4 mmol) is added to the reaction solution at 0 ° C., and the reaction is carried out for 30 minutes to perform CH. ₃ I (312 mg, 30 mmol) was added dropwise, the temperature was naturally raised to room temperature, and the reaction was allowed to proceed overnight. Saturated NH ₄ Cl aqueous solution (50 mL) is added, extracted with ethyl acetate (50 mL × 2), the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and column chromatographed. , The title compound, benzyl ((trans) -2-methoxycyclopentyl) carbamate (300 mg, 60%) was obtained.
MS m / z (ESI): 250.1 [M + H] ⁺ .
Step 3: Preparation of (trans) -2-methoxycyclopentane-1-amine

Benzyl ((trans) -2-methoxycyclopentyl) carbamate (300 mg, 1.2 mmol) is dissolved in methanol (30 mL), 10% Pd / C (60 mg) is added, and the mixture is reacted at room temperature for ₂ hours in an H2 atmosphere. rice field. Filtration and concentration gave the title compound (trans) -2-methoxycyclopentane-1-amine (70 mg, 50%).
MS m / z (ESI): 116.2 [M + H] ⁺ .
Step 4: Preparation of 6-amino-4-(((trans) -2-methoxycyclopentyl) amino) nicotinonitrile

Refer to Intermediate 2 for the method for producing 6-amino-4-(((trans) -2-methoxycyclopentyl) amino) nicotinonitrile.
MS m / z (ESI): 233.2 [M + H] ⁺ .

２－メチルテトラヒドロフラン－３－チオール（１４２ｍｇ、１．２ｍｍｏｌ）をＴＨＦ（５ｍＬ）に溶解して、Ｎ_２雰囲気下でＫＨＭＤＳ（１．２ｍＬ、１．２ｍｍｏｌ）を加え、室温で３０ｍｉｎ撹拌して、６－アミノ－４－フルオロニコチノニトリル（８２．２ｍｇ、０．６ｍｍｏｌ）のＴＨＦ（１ｍＬ）溶液を滴下し、室温で一晩反応させた。飽和ＮＨ_４Ｃｌ水溶液（５０ｍＬ）を加えて、酢酸エチル（５０ｍＬ×２）で抽出し、有機相を飽和食塩水で洗浄して、無水硫酸ナトリウムで乾燥させて濃縮させ、カラムクロマトグラフィーをして、表題化合物である６－アミノ－４－（（２－メチルテトラヒドロフラン－３－イル）チオ）ニコチノニトリル（８０ｍｇ、５７％）を得た。
ＭＳ ｍ／ｚ （ＥＳＩ）： ２３６．１［Ｍ＋Ｈ］^＋． Preparation of Intermediate 7: 6-Amino-4-((2-Methyltetrahydro-3-yl) Thio) Nicotinonitrile

2-Methyltetrahydrofuran-3-thiol (142 mg, 1.2 mmol) is dissolved in THF (5 mL), KHMDS (1.2 mL, 1.2 mmol) is added under an _N2 atmosphere, and the mixture is stirred at room temperature for 30 min. A solution of 6-amino-4-fluoronicotinonitrile (82.2 mg, 0.6 mmol) in THF (1 mL) was added dropwise and reacted overnight at room temperature. Saturated NH ₄ Cl aqueous solution (50 mL) is added, extracted with ethyl acetate (50 mL × 2), the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and column chromatographed. , The title compound 6-amino-4-((2-methyltetra-3-yl) thio) nicotinonitrile (80 mg, 57%) was obtained.
MS m / z (ESI): 236.1 [M + H] ⁺ .

６－アミノ－４－（（２－メトキシフェニル）アミノ）ニコチノニトリルの製造方法は中間体７を参照すればよい。
ＭＳ ｍ／ｚ （ＥＳＩ）： ２４１．１［Ｍ＋Ｈ］^＋． Preparation of Intermediate 8: 6-Amino-4-((2-Methoxyphenyl) Amino) Nicotinonitrile

For the method for producing 6-amino-4-((2-methoxyphenyl) amino) nicotinonitrile, refer to Intermediate 7.
MS m / z (ESI): 241.1 [M + H] ⁺ .

ステップ１：ジベンジルグリシンエチルの製造

ジベンジルアミン（１０．０ｇ、５１ｍｍｏｌ）、ブロモ酢酸エチル（６．７７ｇ、４１ｍｍｏｌ）をエタノール（１００ｍＬ）に溶解して、次に７０℃に加熱して１２時間反応させた。反応液を濃縮させて、残留液をＣＨ_２Ｃｌ_２で溶解した後、飽和ＮＨ_４Ｃｌ水溶液、飽和食塩水を順次洗浄して、無水硫酸ナトリウムで乾燥させて濃縮させ、カラムクロマトグラフィーをして、表題化合物であるジベンジルグリシンエチル（６．５ｇ、５７％）を得た。
ＭＳ ｍ／ｚ （ＥＳＩ）： ２８４．２ ［Ｍ＋Ｈ］^＋．
ステップ２：１－（（ジベンジルアミノ）メチル）シクロプロパン－１－オールの製造

室温で、ジベンジルグリシンエチル（３．０ｇ、１１ｍｍｏｌ）のエーテル溶液（１００ｍＬ）にチタンテトライソプロポキシド（６２２ｍｇ、２．３３ｍｍｏｌ）を加えて、次に臭化エチルマグネシウム（３．０ＭＥｔ_２Ｏ溶液、１０．６ｍＬ、３１．８ｍｍｏｌ）をゆっくりと滴下し、室温で１２時間撹拌して、反応させて０℃に冷却させ、２Ｍ塩酸（１０ｍＬ）をゆっくりと加えて、次に室温にゆっくりと昇温し、さらに３０分間撹拌した。反応液に飽和ＮａＨＣＯ_３水溶液（６０ｍＬ）を加えて、１０分間撹拌後、ＣＨ_２Ｃｌ_２で２回抽出して、濃縮させて、カラムクロマトグラフィーをして、表題化合物である１－（（ジベンジルアミノ）メチル）シクロプロパン－１－オール（１．７ｇ、６０％）を得た。
ＭＳ ｍ／ｚ （ＥＳＩ）： ２６８．２ ［Ｍ＋Ｈ］^＋．
ステップ３：Ｎ,Ｎ－ジベンジル－１－（１－メトキシシクロプロピル）メチルアミンの製造

氷浴下で、１－（（ジベンジルアミノ）メチル）シクロプロパン－１－オール（１．０ｇ、３．７ｍｍｏｌ）のＤＭＦ溶液（１００ｍＬ）に、ＮａＨ（６０％ｉｎｏｉｌ、１７９ｍｇ、４．５ｍｍｏｌ）をバッチ式で加えて、該温度で６０分間撹拌した。次にヨードメタン（５８４ｍｇ、４．１ｍｍｏｌ）を加えて、反応させて室温にゆっくりと昇温し、さらに２時間撹拌した。飽和ＮＨ_４Ｃｌ水溶液（１０ｍＬ）を加え、次に反応液を濃縮させて、残留液をＣＨ_２Ｃｌ_２で溶解した後、飽和ＮＨ_４Ｃｌ水溶液、飽和食塩水を順次洗浄して、無水硫酸ナトリウムで乾燥させて濃縮させ、カラムクロマトグラフィーをして、表題化合物であるＮ,Ｎ－ジベンジル－１－（１－メトキシシクロプロピル）メチルアミン（３５０ｍｇ、３３％）を得た。
ＭＳ ｍ／ｚ （ＥＳＩ）： ２８２．２ ［Ｍ＋Ｈ］^＋．
ステップ４：（１－メトキシシクロプロピル）メチルアミンの製造

窒素保護下で、Ｎ,Ｎ－ジベンジル－１－（１－メトキシシクロプロピル）メチルアミン（３００ｍｇ、１．０７ｍｍｏｌ）のＭｅＯＨ溶液（１０ｍＬ）に酢酸（２ｍＬ）、Ｐｄ（ＯＨ）_２（６０ｍｇ）を加えた。次に反応を水素ガス雰囲気下（５０Ｐｓｉ）で、室温で１２時間撹拌して、次に反応液を濃縮させて、濾過して、表題化合物である（１－メトキシシクロプロピル）メチルアミンを得て、次のステップの反応に直接用いた。
ＭＳ ｍ／ｚ （ＥＳＩ）： １０２．１［Ｍ＋Ｈ］^＋．
ステップ５：６－アミノ－４－（（（１－メトキシシクロプロピル）メチル）アミノ）ニコチノニトリルの製造

６－アミノ－４－（（（１－メトキシシクロプロピル）メチル）アミノ）ニコチノニトリルの製造方法は中間体２を参照すればよい。
ＭＳ ｍ／ｚ （ＥＳＩ）： ２１９．１［Ｍ＋Ｈ］^＋． Preparation of Intermediate 9: 6-Amino-4-(((1-methoxycyclopropyl) Methyl) Amino) Nicotinonitrile

Step 1: Production of dibenzylglycine ethyl

Dibenzylamine (10.0 g, 51 mmol) and ethyl bromoacetate (6.77 g, 41 mmol) were dissolved in ethanol (100 mL), then heated to 70 ° C. and reacted for 12 hours. After concentrating the reaction solution and dissolving the residual solution with CH ₂ Cl ₂ , the saturated NH ₄ Cl aqueous solution and the saturated saline solution are washed in sequence, dried with anhydrous sodium sulfate, concentrated, and subjected to column chromatography. , The title compound, dibenzylglycine ethyl (6.5 g, 57%) was obtained.
MS m / z (ESI): 284.2 [M + H] ⁺ .
Step 2: Preparation of 1-((dibenzylamino) methyl) cyclopropane-1-ol

At room temperature, titanium tetraisopropoxide (622 mg, 2.33 mmol) is added to an ether solution (100 mL) of dibenzylglycine ethyl (3.0 g, 11 mmol), then ethylmagnesium bromide (3.0 MEt _2O solution). (10.6 mL, 31.8 mmol) is slowly added dropwise, stirred at room temperature for 12 hours, reacted to cool to 0 ° C., 2M hydrochloric acid (10 mL) is slowly added, and then slowly rises to room temperature. It was warmed and stirred for an additional 30 minutes. A saturated aqueous solution of NaHCO ₃ (60 mL) is added to the reaction solution, and the mixture is stirred for 10 minutes, extracted twice with CH ₂ Cl ₂ , concentrated, and subjected to column chromatography. Benzylamino) methyl) cyclopropane-1-ol (1.7 g, 60%) was obtained.
MS m / z (ESI): 268.2 [M + H] ⁺ .
Step 3: Preparation of N, N-dibenzyl-1- (1-methoxycyclopropyl) methylamine

NaH (60% inoil, 179 mg, 4.5 mmol) in a DMF solution (100 mL) of 1-((dibenzylamino) methyl) cyclopropane-1-ol (1.0 g, 3.7 mmol) under an ice bath. Was added in batch form and stirred at that temperature for 60 minutes. Next, iodomethane (584 mg, 4.1 mmol) was added, the reaction was carried out, the temperature was slowly raised to room temperature, and the mixture was further stirred for 2 hours. Saturated NH ₄ Cl aqueous solution (10 mL) is added, then the reaction solution is concentrated, the residual solution is dissolved in CH ₂ Cl ₂ , and then the saturated NH ₄ Cl aqueous solution and saturated saline are washed in sequence, and anhydrous sodium sulfate is washed. The mixture was dried in water and concentrated, and column chromatography was performed to obtain the title compound N, N-dibenzyl-1- (1-methoxycyclopropyl) methylamine (350 mg, 33%).
MS m / z (ESI): 282.2 [M + H] ⁺ .
Step 4: Production of (1-methoxycyclopropyl) methylamine

Under nitrogen protection, acetic acid (2 mL) and Pd (OH) ₂ (60 mg) were added to a MeOH solution (10 mL) of N, N-dibenzyl-1- (1-methoxycyclopropyl) methylamine (300 mg, 1.07 mmol). added. The reaction was then stirred in a hydrogen gas atmosphere (50 Psi) at room temperature for 12 hours, then the reaction was concentrated and filtered to give the title compound (1-methoxycyclopropyl) methylamine. , Used directly in the reaction of the next step.
MS m / z (ESI): 102.1 [M + H] ⁺ .
Step 5: Preparation of 6-amino-4-(((1-methoxycyclopropyl) methyl) amino) nicotinonitrile

For the method for producing 6-amino-4-(((1-methoxycyclopropyl) methyl) amino) nicotinonitrile, refer to Intermediate 2.
MS m / z (ESI): 219.1 [M + H] ⁺ .

６－アミノ－４－（（２－シクロプロポキシエチル）アミノ）ニコチノニトリルの製造方法は中間体２を参照すればよい。
ＭＳ ｍ／ｚ （ＥＳＩ）： ２１９．１［Ｍ＋Ｈ］^＋． Preparation of Intermediate 10: 6-Amino-4-((2-Cyclopropoxyethyl) Amino) Nicotinonitrile

For the method for producing 6-amino-4-((2-cyclopropoxyethyl) amino) nicotinonitrile, refer to Intermediate 2.
MS m / z (ESI): 219.1 [M + H] ⁺ .

６－アミノ－４－（（２－（シクロプロピルメトキシ）エチル）アミノ）ニコチノニトリルの製造方法は中間体２を参照すればよい。
ＭＳ ｍ／ｚ （ＥＳＩ）： ２３３．１［Ｍ＋Ｈ］^＋． Preparation of Intermediate 11: 6-Amino-4-((2- (cyclopropylmethoxy) Ethyl) Amino) Nicotinonitrile

For the method for producing 6-amino-4-((2- (cyclopropylmethoxy) ethyl) amino) nicotinonitrile, refer to Intermediate 2.
MS m / z (ESI): 233.1 [M + H] ⁺ .

６－アミノ－４－（（１－（メトキシメチル）シクロプロピル）アミノ）ニコチノニトリルの製造方法は中間体２を参照すればよい。
ＭＳ ｍ／ｚ （ＥＳＩ）： ２１９．１［Ｍ＋Ｈ］^＋． Preparation of Intermediate 12: 6-Amino-4-((1- (Methoxymethyl) Cyclopropyl) Amino) Nicotinonitrile

For the method for producing 6-amino-4-((1- (methoxymethyl) cyclopropyl) amino) nicotinonitrile, refer to Intermediate 2.
MS m / z (ESI): 219.1 [M + H] ⁺ .

６－アミノ－４－（（（シス）－２－メトキシシクロペンチル）アミノ）ニコチノニトリルの製造方法は中間体２を参照すればよい。
ＭＳｍ／ｚ（ＥＳＩ）：２３３．１［Ｍ＋Ｈ］^＋． Preparation of Intermediate 13: 6-Amino-4-(((cis) -2-methoxycyclopentyl) amino) nicotinonitrile

For the method for producing 6-amino-4-(((cis) -2-methoxycyclopentyl) amino) nicotinonitrile, refer to Intermediate 2.
MSm / z (ESI): 233.1 [M + H] ⁺ .

Ｎ４－（２－メトキシエチル）－５－シアノチオピリジン－２,４－ジアミンの製造方法は中間体２を参照すればよい。
ＭＳ ｍ／ｚ （ＥＳＩ）： ２２５．１［Ｍ＋Ｈ］^＋． Intermediate 14: Preparation of N4- (2-methoxyethyl) -5-cyanothiopyridine-2,4-diamine

For the method for producing N4- (2-methoxyethyl) -5-cyanothiopyridine-2,4-diamine, refer to Intermediate 2.
MS m / z (ESI): 225.1 [M + H] ⁺ .

６－アミノ－５－フルオロ－４－（（２－メトキシエチル）アミノ）ニコチノニトリルの製造方法は中間体２を参照すればよい。
ＭＳ ｍ／ｚ （ＥＳＩ）： ２１１．１［Ｍ＋Ｈ］^＋． Preparation of Intermediate 15: 6-Amino-5-Fluoro-4-((2-Methoxyethyl) Amino) Nicotinonitrile

For the method for producing 6-amino-5-fluoro-4-((2-methoxyethyl) amino) nicotinonitrile, refer to Intermediate 2.
MS m / z (ESI): 211.1 [M + H] ⁺ .

６－アミノ－４－（（テトラヒドロフラン－３－イル）チオ）ニコチノニトリルの製造方法は中間体７を参照すればよい。
ＭＳ ｍ／ｚ （ＥＳＩ）： ２２２．１［Ｍ＋Ｈ］^＋． Preparation of Intermediate 16: 6-Amino-4-((Tetrahydrofuran-3-yl) Thio) Nicotinonitrile

For the method for producing 6-amino-4-((tetrahydrofuran-3-yl) thio) nicotinonitrile, refer to Intermediate 7.
MS m / z (ESI): 222.1 [M + H] ⁺ .

６－アミノ－４－（（２－メトキシエチル）チオ）ニコチノニトリルの製造方法は中間体７を参照すればよい。
ＭＳ ｍ／ｚ （ＥＳＩ）： ２１０．１［Ｍ＋Ｈ］^＋． Preparation of Intermediate 17: 6-Amino-4-((2-Methoxyethyl) Thio) Nicotinonitrile

For the method for producing 6-amino-4-((2-methoxyethyl) thio) nicotinonitrile, refer to Intermediate 7.
MS m / z (ESI): 210.1 [M + H] ⁺ .

６－アミノ－４－（（１－メトキシシクロプロピル）メトキシ基）ニコチノニトリルの製造方法は中間体７を参照すればよい。
ＭＳ ｍ／ｚ （ＥＳＩ）： ２２０．２ ［Ｍ＋Ｈ］^＋． Preparation of intermediate 18: 6-amino-4-((1-methoxycyclopropyl) methoxy group) nicotinonitrile

Refer to Intermediate 7 for the method for producing 6-amino-4-((1-methoxycyclopropyl) methoxy group) nicotinonitrile.
MS m / z (ESI): 220.2 [M + H] ⁺ .

６－アミノ－４－（（（トランス）－２－メトキシシクロペンチル）オキソ）ニコチノニトリルの製造方法は中間体７を参照すればよい。
ＭＳ ｍ／ｚ （ＥＳＩ）： ２３４．１［Ｍ＋Ｈ］^＋． Preparation of intermediate 19: 6-amino-4-(((trans) -2-methoxycyclopentyl) oxo) nicotinonitrile

Refer to Intermediate 7 for the method for producing 6-amino-4-(((trans) -2-methoxycyclopentyl) oxo) nicotinonitrile.
MS m / z (ESI): 234.1 [M + H] ⁺ .

（Ｒ）－６－アミノ－４－（（１－メトキシプロパン－２－イル）オキソ）ニコチノニトリルの製造方法は中間体７を参照すればよい。
ＭＳ ｍ／ｚ （ＥＳＩ）： ２０８．１［Ｍ＋Ｈ］^＋． Intermediate 20: Preparation of (R) -6-amino-4-((1-methoxypropan-2-yl) oxo) nicotinonitrile

Refer to Intermediate 7 for the method for producing (R) -6-amino-4-((1-methoxypropane-2-yl) oxo) nicotinonitrile.
MS m / z (ESI): 208.1 [M + H] ⁺ .

ステップ１：２－（ジメトキシメチル）－１,８－ジアゾナフタレンの製造

２－アミノニコチンアルデヒド（２５．０ｇ、２０５ｍｍｏｌ）、１,１－ジメトキシプロパン－２－オン（３１．４ｇ、２６６ｍｍｏｌ）を混合してエタノール（５００ｍＬ）と水（５０ｍＬ）の混合溶媒に溶解して、次にＮａＯＨ水溶液（３Ｍ、８８．７ｍＬ、２６６ｍｍｏｌ）を滴下し、次に室温で３時間撹拌した。反応液を濃縮させて、残留液をＥｔＯＡｃで溶解した後、飽和食塩水で２回洗浄し、無水硫酸ナトリウムで乾燥させて濃縮させ、表題化合物である２－（ジメトキシメチル）－１,８－ジアゾナフタレン（４２．３ｇ）を得て、次のステップの反応に直接用いた。
ステップ２：７－（ジメトキシメチル）－１、２、３,４－テトラヒドロ－１,８－ジアゾナフタレンの製造

２－（ジメトキシメチル）－１,８－ジアゾナフタレン（４２．３ｇ、２０５ｍｍｏｌ）のエタノール溶液（６００ｍＬ）にＰｔＯ_２（１．２５ｇ）を加え、常温常圧の水素雰囲気下で３６時間反応させた後、珪藻土で濾過して触媒を除去した。濾液を濃縮させて、ｘ表題化合物である７－（ジメトキシメチル）－１、２、３,４－テトラヒドロ－１,８－ジアゾナフタレン（４２．７ｇ）を得て、次のステップの反応に直接用いた。
ステップ３：６－ブロモ－７－（ジメトキシメチル）－１,２,３,４－テトラヒドロ－１,８－ジアゾナフタレンの製造

室温下で、７－（ジメトキシメチル）－１,２,３,４－テトラヒドロ－１,８－ジアゾナフタレン（４２．７ｇ、２０５ｍｍｏｌ）のＭｅＣＮ溶液（１Ｌ）に、ＮＢＳ（３８．３ｇ、２１５ｍｍｏｌ）をバッチ式で加え、次に１時間撹拌した。反応液を濃縮させて、残留物をＣＨ_２Ｃｌ_２で溶解した後、１ＭＮａＯＨ水溶液、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥させて濃縮させ、カラムクロマトグラフィーをして、表題化合物である６－ブロモ－７－（ジメトキシメチル）－１,２,３,４－テトラヒドロ－１,８－ジアゾナフタレン（４７．５ｇ、３つのステップの全収率８１％）を得た。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３）： δ ７．２７ （ｓ, １Ｈ）, ５．５５ （ｓ, １Ｈ）, ５．３９ （ｂｒ ｓ, １Ｈ）, ３．４５ （ｓ, ６Ｈ）, ３．３８ （ｍ, ２Ｈ）, ２．７０ （ｔ, Ｊ ＝ ６．０ Ｈｚ, ２Ｈ）, １．８８ （ｍ, ２Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ２８７．０ ［Ｍ＋Ｈ］^＋．
ステップ４：２－（ジメトキシメチル）－５,６,７,８－テトラヒドロ－１,８－ジアゾナフタレン－３－ホルムアルデヒドの製造

－７８℃で、６－ブロモ－７－（ジメトキシメチル）－１,２,３,４－テトラヒドロ－１,８－ジアゾナフタレン（１１４ｍｇ、０．３９７ｍｍｏｌ）のＴＨＦ溶液（３ｍＬ）にＭｅＬｉ（１．６ＭＴＨＦ溶液、０．３０ｍＬ、０．４８ｍｍｏｌ）を滴下した。該温度で撹拌しながら５分間反応させた後、ｎ－ＢｕＬｉ（１．６ＭＴＨＦ溶液、０．５０ｍＬ、０．８０ｍｍｏｌ）を滴下して、該温度で１５分間撹拌し続けた。乾燥ＤＭＦ（０．１２ｍＬ、１．６ｍｍｏｌ）をゆっくりと滴下した。反応を室温にゆっくりと昇温し、次に３０分間撹拌した。反応液に飽和ＮＨ_４Ｃｌ水溶液を加えて、５分間撹拌後、ＣＨ_２Ｃｌ_２で２回抽出して、有機相を合併し、無水硫酸マグネシウムで乾燥させて濃縮させ、カラムクロマトグラフィーをして、表題化合物である２－（ジメトキシメチル）－５,６,７,８－テトラヒドロ－１,８－ジアゾナフタレン－３－ホルムアルデヒド（７３ｍｇ、７８％）を得た。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３）： δ １０．３２ （ｓ, １Ｈ）, ７．７５ （ｓ, １Ｈ）, ５．９３ （ｂｒ ｓ, １Ｈ）, ５．４４ （ｓ, １Ｈ）, ３．４９ （ｍ, ８Ｈ）, ２．７６ （ｔ, Ｊ ＝ ６．０ Ｈｚ, ２Ｈ）, １．９１（ｍ, ２Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ２３７．１［Ｍ＋Ｈ］^＋． Preparation of Intermediate 21: 2- (dimethoxymethyl) -5,6,7,8-tetrahydro-1,8-diazonaphthalene-3-formaldehyde

Step 1: Preparation of 2- (dimethoxymethyl) -1,8-diazonaphthalene

2-Aminonicotinaldehyde (25.0 g, 205 mmol), 1,1-dimethoxypropan-2-one (31.4 g, 266 mmol) is mixed and dissolved in a mixed solvent of ethanol (500 mL) and water (50 mL). Then, an aqueous NaOH solution (3M, 88.7 mL, 266 mmol) was added dropwise, and then the mixture was stirred at room temperature for 3 hours. The reaction was concentrated, the residue was dissolved in EtOAc, washed twice with saturated saline, dried over anhydrous sodium sulfate and concentrated to give the title compound 2- (dimethoxymethyl) -1,8-. Diazonaphthalene (42.3 g) was obtained and used directly in the reaction of the next step.
Step 2: Preparation of 7- (dimethoxymethyl) -1,2,3,4-tetrahydro-1,8-diazonaphthalene

PtO ₂ (1.25 g) was added to an ethanol solution (600 mL) of 2- (dimethoxymethyl) -1,8-diazonaphthalene (42.3 g, 205 mmol), and the mixture was reacted under a hydrogen atmosphere at normal temperature and pressure for 36 hours. After that, the catalyst was removed by filtration through diatomaceous earth. The filtrate is concentrated to give the x title compound 7- (dimethoxymethyl) -1,2,3,4-tetrahydro-1,8-diazonaphthalene (42.7 g), which is directly used in the reaction of the next step. Using.
Step 3: Preparation of 6-bromo-7- (dimethoxymethyl) -1,2,3,4-tetrahydro-1,8-diazonaphthalene

NBS (38.3 g, 215 mmol) in a MeCN solution (1 L) of 7- (dimethoxymethyl) -1,2,3,4-tetrahydro-1,8-diazonaphthalene (42.7 g, 205 mmol) at room temperature. Was added in batch and then stirred for 1 hour. After concentrating the reaction solution and dissolving the residue in CH ₂ Cl ₂ , the mixture was washed successively with 1M NaOH aqueous solution and saturated brine, dried over anhydrous sodium sulfate, concentrated, column chromatographed, and the title compound was used. A certain 6-bromo-7- (dimethoxymethyl) -1,2,3,4-tetrahydro-1,8-diazonaphthalene (47.5 g, total yield of 3 steps 81%) was obtained.
^{1 1} H NMR (400 MHz, CDCl ₃ ): δ 7.27 (s, 1H), 5.55 (s, 1H), 5.39 (br s, 1H), 3.45 (s, 6H), 3 .38 (m, 2H), 2.70 (t, J = 6.0 Hz, 2H), 1.88 (m, 2H);
MS m / z (ESI): 287.0 [M + H] ⁺ .
Step 4: Production of 2- (dimethoxymethyl) -5,6,7,8-tetrahydro-1,8-diazonaphthalene-3-formaldehyde

At −78 ° C., MeLi (1. 6M THF solution, 0.30 mL, 0.48 mmol) was added dropwise. After reacting for 5 minutes with stirring at the temperature, n-BuLi (1.6 MTH F solution, 0.50 mL, 0.80 mmol) was added dropwise, and stirring was continued at the temperature for 15 minutes. Dry DMF (0.12 mL, 1.6 mmol) was slowly added dropwise. The reaction was slowly warmed to room temperature and then stirred for 30 minutes. A saturated aqueous solution of NH ₄ Cl is added to the reaction solution, and the mixture is stirred for 5 minutes, extracted twice with CH ₂ Cl ₂ , mixed with an organic phase, dried over anhydrous magnesium sulfate, concentrated, and subjected to column chromatography. , The title compound 2- (dimethoxymethyl) -5,6,7,8-tetrahydro-1,8-diazonaphthalene-3-formaldehyde (73 mg, 78%) was obtained.
^{1 1} H NMR (400 MHz, CDCl ₃ ): δ 10.32 (s, 1H), 7.75 (s, 1H), 5.93 (br s, 1H), 5.44 (s, 1H), 3 .49 (m, 8H), 2.76 (t, J = 6.0 Hz, 2H), 1.91 (m, 2H);
MS m / z (ESI): 237.1 [M + H] ⁺ .

ステップ１：４－（（２－（ジメトキシメチル）－５,６,７,８－テトラヒドロ－１,８－ジアゾナフタレン－３－イル）メチル）モルホリン－３－オンの製造

２－（ジメトキシメチル）－５,６,７,８－テトラヒドロ－１,８－ジアゾナフタレン－３－ホルムアルデヒド（８．１ｇ、３４．４ｍｍｏｌ）、エチル２－（２－アミノエトキシ）アセテート塩酸（７．５４ｇ、４１．２ｍｍｏｌ）、ＴＥＡ（６．５ｍＬ、４８ｍｍｏｌ）、ＮａＢＨ（ＯＡｃ）_３（１１．６ｇ、５４．９ｍｍｏｌ）をＤＣＥ（１５０ｍＬ）に混合し、Ｎ_２雰囲気下で、室温で一晩反応させ、次に８５℃に昇温して５ｈ反応させ続けた。ジクロロメタン（３００ｍＬ）で希釈して、飽和ＮａＨＣＯ_３水溶液（３００ｍＬ×２）で洗浄し、有機相を飽和食塩水で洗浄して、無水硫酸ナトリウムで乾燥させて濃縮させ、カラムクロマトグラフィーをして、表題化合物である４－（（２－（ジメトキシメチル）－５,６,７,８－テトラヒドロ－１,８－ジアゾナフタレン－３－イル）メチル）モルホリン－３－オン（９．５ｇ、８６％）を得た。
ＭＳ ｍ／ｚ （ＥＳＩ）： ３２２．１［Ｍ＋Ｈ］^＋．
ステップ２：フェニル－７－（ジメトキシメチル）－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－カルボキシラートの製造

４－（（２－（ジメトキシメチル）－５,６,７,８－テトラヒドロ－１,８－ジアゾナフタレン－３－イル）メチル）モルホリン－３－オン（６４２ｍｇ、２ｍｍｏｌ）、ジフェニルカーボネート（６４３ｍｇ、３ｍｍｏｌ）をＴＨＦ（１５ｍＬ）に混合して、Ｎ_２雰囲気下で、－７８℃に冷却させ、ＬｉＨＭＤＳのＴＨＦ（４ｍＬ、４ｍｍｏｌ）溶液を滴下し、室温に自然昇温して一晩反応させた。飽和ＮＨ_４Ｃｌ水溶液（１００ｍＬ）を加えて、酢酸エチル（１００ｍＬ×２）で抽出し、有機相を飽和食塩水で洗浄して、無水硫酸ナトリウムで乾燥させて濃縮させ、カラムクロマトグラフィーをして、表題化合物であるフェニル－７－（ジメトキシメチル）－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－カルボキシラート（４００ｍｇ、４５％）を得た。
ＭＳ ｍ／ｚ （ＥＳＩ）： ４４２．１［Ｍ＋Ｈ］^＋． Intermediate 22: Preparation of phenyl-7- (dimethoxymethyl) -6-((3-carbonylmorpholino) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -carboxylate

Step 1: Preparation of 4-((2- (dimethoxymethyl) -5,6,7,8-tetrahydro-1,8-diazonaphthalene-3-yl) methyl) morpholine-3-one

2- (Dimethoxymethyl) -5,6,7,8-tetrahydro-1,8-diazonaphthalene-3-formaldehyde (8.1 g, 34.4 mmol), ethyl 2- (2-aminoethoxy) acetate hydrochloric acid (7) .54 g, 41.2 mmol), TEA (6.5 mL, 48 mmol), NaBH (OAc) ₃ (11.6 g, 54.9 mmol) mixed with DCE (150 mL), under N ₂ atmosphere, overnight at room temperature. The reaction was carried out, then the temperature was raised to 85 ° C. and the reaction was continued for 5 hours. Dichloromethane (300 mL), washed with saturated aqueous NaHCO ₃ solution (300 mL x 2), the organic phase washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatographed. The title compound 4-((2- (dimethoxymethyl) -5,6,7,8-tetrahydro-1,8-diazonaphthalene-3-yl) methyl) morpholin-3-one (9.5 g, 86%) ) Was obtained.
MS m / z (ESI): 322.1 [M + H] ⁺ .
Step 2: Preparation of phenyl-7- (dimethoxymethyl) -6-((3-carbonylmorpholino) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -carboxylate

4-((2- (Dimethoxymethyl) -5,6,7,8-tetrahydro-1,8-diazonaphthalene-3-yl) methyl) morpholine-3-one (642 mg, 2 mmol), diphenyl carbonate (643 mg, 3 mmol) was mixed with THF (15 mL), cooled to −78 ° C. under an _N2 atmosphere, a solution of LiHMDS in THF (4 mL, 4 mmol) was added dropwise, and the mixture was naturally heated to room temperature and reacted overnight. .. Saturated NH ₄ Cl aqueous solution (100 mL) is added, extracted with ethyl acetate (100 mL × 2), the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and column chromatographed. , The title compound, phenyl-7- (dimethoxymethyl) -6-((3-carbonylmorpholino) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -carboxylate (400 mg, 45). %) Was obtained.
MS m / z (ESI): 442.1 [M + H] ⁺ .

ステップ１：エチル２－（３－（（（２－（ジメトキシメチル）－５,６,７,８－テトラヒドロ－１,８－ジアゾナフタレン－３－イル）メチル）アミノ）プロポキシ）アセテートの製造

２－（ジメトキシメチル）－５,６,７,８－テトラヒドロ－１,８－ジアゾナフタレン－３－ホルムアルデヒド（１１８ｍｇ、０．５ｍｍｏｌ）、エチル２－（３－アミノプロポキシ）アセテート塩酸（１１８．２ｍｇ、０．６ｍｍｏｌ）、ＴＥＡ（０．１５ｍＬ、０．７ｍｍｏｌ）、ＮａＢＨ（ＯＡｃ）_３（１６９．６ｍｇ、０．８ｍｍｏｌ）をＤＣＥ（３ｍＬ）に混合して、Ｎ_２雰囲気下で、室温で一晩反応させた。ジクロロメタン（３０ｍＬ）で希釈して、飽和ＮａＨＣＯ_３水溶液（３０ｍＬ×２）で洗浄し、有機相を飽和食塩水で洗浄して、無水硫酸ナトリウムで乾燥させて濃縮させ、カラムクロマトグラフィーをして、表題化合物であるエチル２－（３－（（（２－（ジメトキシメチル）－５,６,７,８－テトラヒドロ－１,８－ジアゾナフタレン－３－イル）メチル）アミノ）プロポキシ）アセテート（１７７ｍｇ、９３％）を得た。
ＭＳ ｍ／ｚ （ＥＳＩ）： ３８２．１［Ｍ＋Ｈ］^＋．
ステップ２：２－（３－（（（２－（ジメトキシメチル）－５,６,７,８－テトラヒドロ－１,８－ジアゾナフタレン－３－イル）メチル）アミノ）プロポキシ）酢酸の製造

エチル－２－（３－（（（２－（ジメトキシメチル）－５,６,７,８－テトラヒドロ－１,８－ジアゾナフタレン－３－イル）メチル）アミノ）プロポキシ）アセテート（１７６．６ｍｇ、０．４６ｍｍｏｌ）、ＬｉＯＨ（４２ｍｇ、１ｍｍｏｌ）をメタノール／ＴＨＦ／水（体積比：２／１／１、２ｍＬ）に混合して、室温で一晩反応させた。反応液を濃縮させて、表題化合物である２－（３－（（（２－（ジメトキシメチル）－５,６,７,８－テトラヒドロ－１,８－ジアゾナフタレン－３－イル）メチル）アミノ）プロポキシ）酢酸粗製品（２００ｍｇ）を得た。
ＭＳ ｍ／ｚ （ＥＳＩ）： ３５４．１［Ｍ＋Ｈ］^＋．
ステップ３：４－（（２－（ジメトキシメチル）－５,６,７,８－テトラヒドロ－１,８－ジアゾナフタレン－３－イル）メチル）－１,４－オキサゼパン－３－オンの製造

２－（３－（（（２－（ジメトキシメチル）－５,６,７,８－テトラヒドロ－１,８－ジアゾナフタレン－３－イル）メチル）アミノ）プロポキシ）酢酸（２００ｍｇ、０．４６ｍｍｏｌ）、ＨＡＴＵ（３８０ｍｇ、１ｍｍｏｌ）、ＤＩＰＥＡ（０．２６ｍＬ、１．５ｍｍｏｌ）をＤＭＦ（５ｍＬ）に混合して、室温で２ｈ反応させた。飽和ＮａＨＣＯ_３水溶液（５０ｍＬ）を加えて、酢酸エチル（５０ｍＬ×２）で抽出し、有機相を飽和食塩水で洗浄して、無水硫酸ナトリウムで乾燥させて濃縮させ、カラムクロマトグラフィーをして、表題化合物である４－（（２－（ジメトキシメチル）－５,６,７,８－テトラヒドロ－１,８－ジアゾナフタレン－３－イル）メチル）－１,４－オキサゼパン－３－オン（１００ｍｇ、６０％）を得た。
ＭＳ ｍ／ｚ （ＥＳＩ）： ３３６．１［Ｍ＋Ｈ］^＋．
ステップ４：フェニル－７－（ジメトキシメチル）－６－（（３－カルボニル－１,４－オキサゼパン－４－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－カルボキシラートの製造

フェニル－７－（ジメトキシメチル）－６－（（３－カルボニル－１,４－オキサゼパン－４－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－カルボキシラートの製造方法は中間体２２を参照すればよい。
ＭＳ ｍ／ｚ （ＥＳＩ）： ４５６．１［Ｍ＋Ｈ］^＋． Intermediate 23: Phenyl-7- (dimethoxymethyl) -6-((3-carbonyl-1,4-oxazepan-4-yl) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) ) -Manufacture of carboxylate

Step 1: Preparation of 3-(((2- (dimethoxymethyl) -5,6,7,8-tetrahydro-1,8-diazonaphthalene-3-yl) methyl) amino) propoxy) acetate

2- (Dimethoxymethyl) -5,6,7,8-tetrahydro-1,8-diazonaphthalene-3-formaldehyde (118 mg, 0.5 mmol), ethyl 2- (3-aminopropoxy) acetate hydrochloride (118.2 mg) , 0.6 mmol), TEA (0.15 mL, 0.7 mmol), NaBH (OAc) ₃ (169.6 mg, 0.8 mmol) mixed with DCE (3 mL) in an _N2 atmosphere at room temperature. It was reacted in the evening. Dichloromethane (30 mL), washed with saturated aqueous NaHCO ₃ solution (30 mL x 2), the organic phase washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, column chromatographically performed. The title compound, ethyl 2-(3-(((2- (dimethoxymethyl) -5,6,7,8-tetrahydro-1,8-diazonaphthalene-3-yl) methyl) amino) propoxy) acetate (177 mg) , 93%).
MS m / z (ESI): 382.1 [M + H] ⁺ .
Step 2: Preparation of 2-(3-(((2- (dimethoxymethyl) -5,6,7,8-tetrahydro-1,8-diazonaphthalene-3-yl) methyl) amino) propoxy) acetic acid

Ethyl-2-(3-(((2- (dimethoxymethyl) -5,6,7,8-tetrahydro-1,8-diazonaphthalene-3-yl) methyl) amino) propoxy) acetate (176.6 mg, 0.46 mmol) and LiOH (42 mg, 1 mmol) were mixed with methanol / THF / water (volume ratio: 2/1/1, 2 mL) and reacted overnight at room temperature. The reaction mixture was concentrated to give the title compound 2-(3-(((2- (dimethoxymethyl) -5,6,7,8-tetrahydro-1,8-diazonaphthalene-3-yl) methyl) methyl) amino. ) Propoxy) A crude acetic acid product (200 mg) was obtained.
MS m / z (ESI): 354.1 [M + H] ⁺ .
Step 3: Preparation of 4-((2- (dimethoxymethyl) -5,6,7,8-tetrahydro-1,8-diazonaphthalene-3-yl) methyl) -1,4-oxazepan-3-one

2-(3-(((2- (dimethoxymethyl) -5,6,7,8-tetrahydro-1,8-diazonaphthalene-3-yl) methyl) amino) propoxy) acetic acid (200 mg, 0.46 mmol) , HATU (380 mg, 1 mmol) and DIPEA (0.26 mL, 1.5 mmol) were mixed with DMF (5 mL) and reacted at room temperature for 2 hours. Saturated NaHCO ₃ aqueous solution (50 mL) was added, extracted with ethyl acetate (50 mL × 2), the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and column chromatographed. The title compound 4-((2- (dimethoxymethyl) -5,6,7,8-tetrahydro-1,8-diazonaphthalene-3-yl) methyl) -1,4-oxazepan-3-one (100 mg) , 60%).
MS m / z (ESI): 336.1 [M + H] ⁺ .
Step 4: Phenyl-7- (dimethoxymethyl) -6-((3-carbonyl-1,4-oxazepan-4-yl) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -Manufacture of carboxylate

Phenyl-7- (dimethoxymethyl) -6-((3-carbonyl-1,4-oxazepan-4-yl) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -carboxylate 22 may be referred to for the method of producing the above.
MS m / z (ESI): 456.1 [M + H] ⁺ .

フェニル－７－（ジメトキシメチル）－６－（（４－メチル－２－カルボニル－１,４－ジアゼパン－１－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－カルボキシラートの製造方法は中間体２を参照すればよい３。
ＭＳ ｍ／ｚ （ＥＳＩ）： ４６９．１［Ｍ＋Ｈ］^＋． Intermediate 24: Phenyl-7- (dimethoxymethyl) -6-((4-methyl-2-carbonyl-1,4-diazepan-1-yl) methyl) -3,4-dihydro-1,8-diazonaphthalene Production of -1 (2H) -carboxylate

Phenyl-7- (dimethoxymethyl) -6-((4-methyl-2-carbonyl-1,4-diazepan-1-yl) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) ) -For the method for producing carboxylate, refer to Intermediate 2. 3.
MS m / z (ESI): 469.1 [M + H] ⁺ .

フェニル（Ｓ）－７－（ジメトキシメチル）－６－（（４－メチル－２－カルボニルオキサゾリジン－３－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－カルボキシラートの製造方法は中間体２２を参照すればよい。
ＭＳ ｍ／ｚ （ＥＳＩ）： ４４２．２ ［Ｍ＋Ｈ］^＋． Intermediate 25: Phenyl (S) -7- (dimethoxymethyl) -6-((4-methyl-2-carbonyloxazolidine-3-yl) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -Manufacture of carboxylate

Phenyl (S) -7- (dimethoxymethyl) -6-((4-methyl-2-carbonyloxazolidine-3-yl) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H)- For the method for producing carboxylate, refer to Intermediate 22.
MS m / z (ESI): 442.2 [M + H] ⁺ .

フェニル－７－（ジメトキシメチル）－６－（（８－カルボニル－４－オキサ－７－アザスピロ［２．５］オクタン－７－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－カルボキシラートの製造方法は中間体２２を参照すればよい。
ＭＳ ｍ／ｚ （ＥＳＩ）： ４６８．２ ［Ｍ＋Ｈ］^＋． Intermediate 26: Phenyl-7- (dimethoxymethyl) -6-((8-carbonyl-4-oxa-7-azaspiro [2.5] octane-7-yl) methyl) -3,4-dihydro-1, Production of 8-diazonaphthalene-1 (2H) -carboxylate

Phenyl-7- (dimethoxymethyl) -6-((8-carbonyl-4-oxa-7-azaspiro [2.5] octane-7-yl) methyl) -3,4-dihydro-1,8-diazonaphthalene For the method for producing -1 (2H) -carboxylate, refer to Intermediate 22.
MS m / z (ESI): 468.2 [M + H] ⁺ .

フェニル－７－（ジメトキシメチル）－６－（（６－カルボニル－４－オキサ－７－アザスピロ［２．５］オクタン－７－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－カルボキシラートの製造方法は中間体２２を参照すればよい。
ＭＳ ｍ／ｚ （ＥＳＩ）： ４６８．２ ［Ｍ＋Ｈ］^＋． Intermediate 27: Phenyl-7- (dimethoxymethyl) -6-((6-carbonyl-4-oxa-7-azaspiro [2.5] octane-7-yl) methyl) -3,4-dihydro-1, Production of 8-diazonaphthalene-1 (2H) -carboxylate

Phenyl-7- (dimethoxymethyl) -6-((6-carbonyl-4-oxa-7-azaspiro [2.5] octane-7-yl) methyl) -3,4-dihydro-1,8-diazonaphthalene For the method for producing -1 (2H) -carboxylate, refer to Intermediate 22.
MS m / z (ESI): 468.2 [M + H] ⁺ .

フェニル－７－（ジメトキシメチル）－６－（（５－カルボニル－７－オキサ－４－アザスピロ［２．５］オクタン－４－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－カルボキシラートの製造方法は中間体２２を参照すればよい。
ＭＳ ｍ／ｚ （ＥＳＩ）： ４６８．２ ［Ｍ＋Ｈ］^＋． Intermediate 28: Phenyl-7- (dimethoxymethyl) -6-((5-carbonyl-7-oxa-4-azaspiro [2.5] octane-4-yl) methyl) -3,4-dihydro-1, Production of 8-diazonaphthalene-1 (2H) -carboxylate

Phenyl-7- (dimethoxymethyl) -6-((5-carbonyl-7-oxa-4-azaspiro [2.5] octane-4-yl) methyl) -3,4-dihydro-1,8-diazonaphthalene For the method for producing -1 (2H) -carboxylate, refer to Intermediate 22.
MS m / z (ESI): 468.2 [M + H] ⁺ .

ステップ１：４－（（（２－（ジメトキシメチル）－５,６,７,８－テトラヒドロ－１,８－ジアゾナフタレン－３－イル）メチル）アミノ）ブタン－１－オールの製造

室温下で、２－（ジメトキシメチル）－５,６,７,８－テトラヒドロ－１,８－ジアゾナフタレン－３－ホルムアルデヒド（１．０ｇ、４．２ｍｍｏｌ）、４－アミノブタン－１－オール（０．４５ｇ、５．１ｍｍｏｌ）をＤＣＥ（１５ｍＬ）に溶解して、２時間撹拌し、次にＮａＢＨ（ＯＡｃ）_３（１．３５ｇ、６．４ｍｍｏｌ）を加えて、室温で一晩撹拌した。反応液をＣＨ_２Ｃｌ_２（１００ｍＬ）で希釈して、有機相を水（１０ｍＬ）と飽和食塩水（１５ｍＬ）で順次洗浄し、無水硫酸ナトリウムで乾燥させて濃縮させ、カラムクロマトグラフィーをして、化合物である４－（（（２－（ジメトキシメチル）－５,６,７,８－テトラヒドロ－１,８－ジアゾナフタレン－３－イル）メチル）アミノ）ブタン－１－オール（０．９ｇ、６９％）を得た。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ ７．１３ （ｓ, １Ｈ）, ５．１７ （ｓ, １Ｈ）, ４．８４ （ｓ, １Ｈ）, ３．７３ （ｓ, ２Ｈ）, ３．６６－３．４９ （ｍ, ２Ｈ）, ３．４２ （ｓ, ６Ｈ）, ３．４０－３．３６ （ｍ, ２Ｈ）, ２．７１（ｔ, Ｊ ＝ ６．３ Ｈｚ, ２Ｈ）, ２．６８－２．５６ （ｍ, ２Ｈ）, １．９５－１．８１（ｍ, ２Ｈ）, １．７４－１．５５ （ｍ, ４Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ３１０．２ ［Ｍ＋Ｈ］^＋．
ステップ２：３－（（２－（ジメトキシメチル）－５,６,７,８－テトラヒドロ－１,８－ジアゾナフタレン－３－イル）メチル）－１,３－オキサゼパン－２－オンの製造

氷水浴下で、４－（（（２－（ジメトキシメチル）－５,６,７,８－テトラヒドロ－１,８－ジアゾナフタレン－３－イル）メチル）アミノ）ブタン－１－オール（０．６ｇ、１．９４ｍｍｏｌ）をＤＣＥ（１５ｍＬ）に溶解して、次にビス（トリクロロメチル）炭酸エステル（０．２２ｇ、０．７６ｍｍｏｌ）を加え、トリエチルアミン（０．７８ｇ、７．７６ｍｍｏｌ）をゆっくりと滴下して、次に室温で３時間撹拌した。反応温度を８０℃に上げて、８０℃で６時間反応させ、反応を室温に冷却させた後、ＣＨ_２Ｃｌ_２（１００ｍＬ）で希釈して、有機相を水（１０ｍＬ）と飽和食塩水（１５ｍＬ）で順次洗浄し、無水硫酸ナトリウムで乾燥させて濃縮させ、カラムクロマトグラフィーをして、化合物である３－（（２－（ジメトキシメチル）－５,６,７,８－テトラヒドロ－１,８－ジアゾナフタレン－３－イル）メチル）－１,３－オキサゼパン－２－オン（０．３７ｇ、５７％）を得た。
ＭＳ ｍ／ｚ （ＥＳＩ）： ３３６．２ ［Ｍ＋Ｈ］^＋．
ステップ３：フェニル－７－（ジメトキシメチル）－６－（（２－カルボニル－１,３－オキサゼパン－３－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－カルボキシラートの製造

７－（ジメトキシメチル）－６－（（２－カルボニル－１,３－オキサゼパン－３－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－カルボキシラートの製造方法は中間体２３のステップ４を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ ７．５６ （ｓ, １Ｈ）, ７．３８（ｍ, ２Ｈ）, ７．２１（ｍ, ３Ｈ）, ５．２２ （ｓ, １Ｈ）, ４．７７ （ｓ, ２Ｈ）, ４．１６ （ｍ, ２Ｈ）, ３．９５ （ｍ, ２Ｈ）, ３．３９ （ｓ, ６Ｈ）, ３．２５ （ｍ, ２Ｈ）, ２．８４ （ｔ, Ｊ ＝ ６．５ Ｈｚ, ２Ｈ）, １．８７ （ｍ, ２Ｈ）, １．６４ （ｍ, ４Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ４５６．２ ［Ｍ＋Ｈ］^＋． Intermediate 29: Phenyl-7- (dimethoxymethyl) -6-((2-carbonyl-1,3-oxazepan-3-yl) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) ) -Manufacture of carboxylate

Step 1: 4-(((2- (dimethoxymethyl) -5,6,7,8-tetrahydro-1,8-diazonaphthalene-3-yl) methyl) amino) butane-1-ol

At room temperature, 2- (dimethoxymethyl) -5,6,7,8-tetrahydro-1,8-diazonaphthalene-3-formaldehyde (1.0 g, 4.2 mmol), 4-aminobutane-1-ol (0). .45 g, 5.1 mmol) was dissolved in DCE (15 mL) and stirred for 2 hours, then NaBH (OAc) ₃ (1.35 g, 6.4 mmol) was added and stirred overnight at room temperature. The reaction mixture is diluted with CH ₂ Cl ₂ (100 mL), the organic phase is washed successively with water (10 mL) and saturated saline (15 mL), dried over anhydrous sodium sulfate, concentrated, and column chromatographed. , Compound 4-(((2- (dimethoxymethyl) -5,6,7,8-tetrahydro-1,8-diazonaphthalene-3-yl) methyl) amino) butane-1-ol (0.9 g) , 69%).
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 7.13 (s, 1H), 5.17 (s, 1H), 4.84 (s, 1H), 3.73 (s, 2H), 3.66 -3.49 (m, 2H), 3.42 (s, 6H), 3.40-3.36 (m, 2H), 2.71 (t, J = 6.3 Hz, 2H), 2. 68-2.56 (m, 2H), 1.95-1.81 (m, 2H), 1.74-1.55 (m, 4H);
MS m / z (ESI): 310.2 [M + H] ⁺ .
Step 2: Preparation of 3-((2- (dimethoxymethyl) -5,6,7,8-tetrahydro-1,8-diazonaphthalene-3-yl) methyl) -1,3-oxazepan-2-one

4-(((2- (Dimethoxymethyl) -5,6,7,8-tetrahydro-1,8-diazonaphthalene-3-yl) methyl) amino) butane-1-ol (0. 6 g (1.94 mmol) is dissolved in DCE (15 mL), then bis (trichloromethyl) carbonate (0.22 g, 0.76 mmol) is added and triethylamine (0.78 g, 7.76 mmol) is slowly added. It was added dropwise and then stirred at room temperature for 3 hours. The reaction temperature was raised to 80 ° C., the reaction was carried out at 80 ° C. for 6 hours, the reaction was cooled to room temperature, diluted with CH ₂ Cl ₂ (100 mL), and the organic phase was diluted with water (10 mL) and saturated saline (10 mL). It was washed successively with (15 mL), dried over anhydrous sodium sulfate, concentrated, column chromatographed and compounded 3-((2- (dimethoxymethyl) -5,6,7,8-tetrahydro-1,2, 8-Diazonaphthalene-3-yl) methyl) -1,3-oxazepan-2-one (0.37 g, 57%) was obtained.
MS m / z (ESI): 336.2 [M + H] ⁺ .
Step 3: Phenyl-7- (dimethoxymethyl) -6-((2-carbonyl-1,3-oxazepan-3-yl) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -Manufacture of carboxylate

Production of 7- (dimethoxymethyl) -6-((2-carbonyl-1,3-oxazepan-3-yl) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -carboxylate The method may refer to step 4 of the intermediate 23.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 7.56 (s, 1H), 7.38 (m, 2H), 7.21 (m, 3H), 5.22 (s, 1H), 4.77 (S, 2H), 4.16 (m, 2H), 3.95 (m, 2H), 3.39 (s, 6H), 3.25 (m, 2H), 2.84 (t, J = 6.5 Hz, 2H), 1.87 (m, 2H), 1.64 (m, 4H);
MS m / z (ESI): 456.2 [M + H] ⁺ .

室温下で、６－アミノ－４－フルオロニコチノニトリル（１．５ｇ、１０．９ｍｍｏｌ）、（Ｒ）－１－メトキシプロパン－２－アミン（１．２ｇ、１３ｍｍｏｌ）をＤＭＡ（１０ｍＬ）に溶解して、ＤＩＰＥＡ（４．２ｇ、３３ｍｍｏｌ）を加え、１３０℃に昇温した。反応液をこの温度で１２時間撹拌して、濃縮後、カラムクロマトグラフィーをして、化合物である（Ｒ）－６－アミノ－４－（（１－メトキシプロパン－２－イル）アミノ）ニコチノニトリル（２ｇ、８９％）を得た。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＤＭＳＯ） δ ７．９４ （ｓ, １Ｈ）, ６．４１（ｓ, ２Ｈ）, ５．７５ （ｄ, Ｊ ＝ ８．２ Ｈｚ, １Ｈ）, ５．６６ （ｓ, １Ｈ）, ３．７０－３．６０ （ｍ, １Ｈ）, ３．４５－３．４０ （ｍ, １Ｈ）, ３．３５－３．３２ （ｍ, １Ｈ）, ３．２８ （ｓ, ３Ｈ）, １．１４ （ｄ, Ｊ ＝ ６．５ Ｈｚ, ３Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ２０７．１［Ｍ＋Ｈ］^＋． Intermediate 30: Preparation of (R) -6-amino-4-((1-methoxypropan-2-yl) amino) nicotinonitrile

At room temperature, 6-amino-4-fluoronicotinonitrile (1.5 g, 10.9 mmol) and (R) -1-methoxypropan-2-amine (1.2 g, 13 mmol) are dissolved in DMA (10 mL). Then, DIPEA (4.2 g, 33 mmol) was added, and the temperature was raised to 130 ° C. The reaction mixture is stirred at this temperature for 12 hours, concentrated, and then column chromatographed to obtain the compound (R) -6-amino-4-((1-methoxypropan-2-yl) amino) nicotino. Nitrile (2 g, 89%) was obtained.
^{1 1} H NMR (400 MHz, DMSO) δ 7.94 (s, 1H), 6.41 (s, 2H), 5.75 (d, J = 8.2 Hz, 1H), 5.66 (s, 1H), 3.70-3.60 (m, 1H), 3.45-3.40 (m, 1H), 3.35-3.32 (m, 1H), 3.28 (s, 3H) , 1.14 (d, J = 6.5 Hz, 3H);
MS m / z (ESI): 207.1 [M + H] ⁺ .

３,７－ジオキサビシクロ［４．１．０］ヘプタン（５００ｍｇ、５．０ｍｍｏｌ）を０．２ＮＨ_２ＳＯ_４のＭｅＯＨ溶液（４６ｍＬ）に溶解して、室温で２時間撹拌した。反応液を重炭酸ナトリウム水溶液（２０ｍＬ）で中和した後に、濃縮させて大部分のメタノールを除去し、酢酸エチル（２０ｍＬ×３）で抽出し、有機相を飽和食塩水で洗浄して、無水硫酸ナトリウムで乾燥させて濃縮させ、カラムクロマトグラフィーをして、表題化合物である（３,４）－トランス－３－メトキシテトラヒドロ－２Ｈ－ピラン－４－オール及び（３,４）－トランス－４－メトキシテトラヒドロ－２Ｈ－ピラン－３－オール混合物（２６０ｍｇ、比率約３：７、収率：３９％）を得た。
中間体３２：（３,４）－トランス－４－メトキシテトラヒドロ－２Ｈ－ピラン－３－アミンの製造

ステップ１：（３,４）－トランス－３－アジドテトラヒドロ－２Ｈ－ピラン－４－オールの製造

３,７－ジオキサビシクロ［４．１．０］ヘプタン（５００ｍｇ、５．０ｍｍｏｌ）、ＮａＮ_３（１．６ｇ、２５．０ｍｍｏｌ）、塩化アンモニウム（５３５ｍｇ、１０．０ｍｍｏｌ）をＭｅＯＨの水溶液（５０ｍＬ、ｖ／ｖ＝１：８）に混合し、窒素雰囲気下で、８０℃で４時間撹拌した。反応液を重炭酸ナトリウム水溶液（５０ｍＬ）で中和した後、酢酸エチル（５０ｍＬ×３）で抽出し、有機相を合併して飽和食塩水で洗浄して、無水硫酸ナトリウムで乾燥させて濃縮させ、カラムクロマトグラフィーで精製して、（３,４）－トランス－３－アジドテトラヒドロ－２Ｈ－ピラン－４－オール（２８０ｍｇ、３９％）を得た。
ステップ２：（３,４）－トランス－３－アジド－４－メトキシテトラヒドロ－２Ｈ－ピランの製造

（３,４）－トランス－３－アジドテトラヒドロ－２Ｈ－ピラン－４－オール（２８０ｍｇ、２．０ｍｍｏｌ）を、乾燥ＴＨＦ（５ｍＬ）に溶解して、反応フラスコを窒素雰囲気下での氷水浴に入れて、ＮａＨ（１２０ｍｇ、３．０ｍｍｏｌ）をバッチ式で加えた。反応温度を室温にゆっくりと昇温し、次に３０ｍｉｎ反応させ、さらに反応液を氷水浴で冷却させて、ＣＨ_３Ｉ（０．４ｍＬ、６．０ｍｍｏｌ）を滴下し、室温に昇温して４０ｍｉｎ撹拌した。反応液を酢酸エチル（１０ｍＬ）で希釈し、飽和ＮａＨＣＯ_３水溶液（１５ｍＬ）を加えて分液し、水相を酢酸エチル（１０ｍＬ×３）で抽出して、有機相を合併し、飽和食塩水で洗浄して、無水硫酸ナトリウムで乾燥させて濃縮させ、カラムクロマトグラフィーをして、（３,４）－トランス－３－アジド－４－メトキシテトラヒドロ－２Ｈ－ピラン（２３０ｍｇ、７５％）を得た。
ステップ３：：（３,４）－トランス－４－メトキシテトラヒドロ－２Ｈ－ピラン－３－アミンの製造

（３,４）－トランス－３－アジド－４－メトキシテトラヒドロ－２Ｈ－ピラン（２３０ｍｇ、１．５ｍｍｏｌ）を、ＭｅＯＨ（６ｍＬ）に溶解して、１０％Ｐｄ／Ｃ（２３ｍｇ）を加えた。水素雰囲気下で、室温で４ｈ反応させた。反応液を濾過して、濾過ケーキをＭｅＯＨ（３ｍＬ）で３回洗浄して、濾液を合併し、濃縮させて表題化合物である（３,４）－トランス－４－メトキシテトラヒドロ－２Ｈ－ピラン－３－アミン（１７８ｍｇ、９３％）を得た。
ＭＳ ｍ／ｚ （ＥＳＩ）： １３２．２ ［Ｍ＋Ｈ］^＋． Intermediate 31: Preparation of (3,4) -trans-3-methoxytetrahydro-2H-pyran-4-ol and (3,4) -trans-4-methoxytetrahydro-2H-pyran-3-ol

3,7-Dioxabicyclo [4.1.0] heptane (500 mg, 5.0 mmol) was dissolved in 0.2 NH ₂ SO ₄ MeOH solution (46 mL) and stirred at room temperature for 2 hours. The reaction is neutralized with an aqueous sodium bicarbonate solution (20 mL) and then concentrated to remove most of the methanol, extracted with ethyl acetate (20 mL x 3), the organic phase washed with saturated saline and anhydrous. It is dried over sodium sulfate, concentrated, column chromatographed and the title compounds (3,4) -trans-3-methoxytetrahydro-2H-pyran-4-ol and (3,4) -trans-4. A mixture of -methoxytetrahydro-2H-pyran-3-ol (260 mg, ratio of about 3: 7, yield: 39%) was obtained.
Intermediate 32: Preparation of (3,4) -trans-4-methoxytetrahydro-2H-pyran-3-amine

Step 1: Preparation of (3,4) -trans-3-azidotetrahydro-2H-pyran-4-ol

3,7-Dioxabicyclo [4.1.0] heptane (500 mg, 5.0 mmol), NaN ₃ (1.6 g, 25.0 mmol), ammonium chloride (535 mg, 10.0 mmol) in aqueous solution of MeOH (50 mL) , V / v = 1: 8) and stirred at 80 ° C. for 4 hours under a nitrogen atmosphere. The reaction mixture is neutralized with an aqueous sodium bicarbonate solution (50 mL), extracted with ethyl acetate (50 mL x 3), combined with the organic phase, washed with saturated saline, dried over anhydrous sodium sulfate and concentrated. , Purified by column chromatography to give (3,4) -trans-3-azidotetrahydro-2H-pyran-4-ol (280 mg, 39%).
Step 2: Preparation of (3,4) -trans-3-azido-4-methoxytetrahydro-2H-pyran

(3,4) -Trans-3-azidotetrahydro-2H-pyran-4-ol (280 mg, 2.0 mmol) is dissolved in dry THF (5 mL) and the reaction flask is placed in an ice water bath under a nitrogen atmosphere. And NaH (120 mg, 3.0 mmol) was added in batch form. The reaction temperature is slowly raised to room temperature, then the reaction is carried out for 30 minutes, the reaction solution is further cooled in an ice-water bath, CH _3I (0.4 mL, 6.0 mmol) is added dropwise, and the reaction temperature is raised to room temperature. The mixture was stirred for 40 minutes. The reaction mixture is diluted with ethyl acetate (10 mL), saturated aqueous NaHCO ₃ solution (15 mL) is added to separate the solutions, the aqueous phase is extracted with ethyl acetate (10 mL × 3), the organic phase is combined, and the saturated saline solution is added. Washed with anhydrous sodium sulfate, concentrated, and column chromatographed to give (3,4) -trans-3-azido-4-methoxytetrahydro-2H-pyran (230 mg, 75%). rice field.
Step 3 :: Production of (3,4) -trans-4-methoxytetrahydro-2H-pyran-3-amine

(3,4) -Trans-3-azido-4-methoxytetrahydro-2H-pyran (230 mg, 1.5 mmol) was dissolved in MeOH (6 mL) and 10% Pd / C (23 mg) was added. The reaction was carried out at room temperature for 4 hours in a hydrogen atmosphere. The reaction was filtered, the filtered cake was washed 3 times with MeOH (3 mL), the filtrate was mixed and concentrated to the title compound (3,4) -trans-4-methoxytetrahydro-2H-pyran-. 3-Amine (178 mg, 93%) was obtained.
MS m / z (ESI): 132.2 [M + H] ⁺ .

Production of Example Compounds

ステップ１：Ｎ－（５－シアノ－４－（（（トランス）－２－メトキシシクロペンチル）アミノ）ピリジン－２－イル）－７－（ジメトキシメチル）－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造

６－アミノ－４－（（（トランス）－２－メトキシシクロペンチル）アミノ）ニコチノニトリル（２０ｍｇ、０．０９ｍｍｏｌ）、フェニル－７－（ジメトキシメチル）－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－カルボキシラート（３８ｍｇ、０．０９ｍｍｏｌ）をＴＨＦ（５ｍＬ）に混合して、Ｎ_２雰囲気下で、－７８℃に冷却させ、ＬｉＨＭＤＳのＴＨＦ（０．２ｍＬ、０．２ｍｍｏｌ）溶液に滴下して、室温に自然昇温して一晩反応させた。飽和ＮＨ_４Ｃｌ水溶液（５０ｍＬ）を加えて、酢酸エチル（５０ｍＬ×２）で抽出し、有機相を飽和食塩水で洗浄して、無水硫酸ナトリウムで乾燥させて濃縮させ、カラムクロマトグラフィーをして、表題化合物であるＮ－（５－シアノ－４－（（（トランス）－２－メトキシシクロペンチル）アミノ）ピリジン－２－イル）－７－（ジメトキシメチル）－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミド（２３ｍｇ、４６％）を得た。
ＭＳ ｍ／ｚ （ＥＳＩ）： ５８０．２ ［Ｍ＋Ｈ］^＋．
ステップ２：Ｎ－（５－シアノ－４－（（（トランス）－２－メトキシシクロペンチル）アミノ）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造

Ｎ－（５－シアノ－４－（（（トランス）－２－メトキシシクロペンチル）アミノ）ピリジン－２－イル）－７－（ジメトキシメチル）－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミド（２３ｍｇ、０．０４ｍｍｏｌ）をＴＨＦ／水（体積比：１１／４、１．５ｍＬ）に溶解して、濃ＨＣｌ（０．１５ｍＬ、１．８ｍｍｏｌ）を加え、室温で２ｈ反応させた。飽和ＮａＨＣＯ_３水溶液（５０ｍＬ）を加えて、酢酸エチル（５０ｍＬ×２）で抽出し、有機相を飽和食塩水で洗浄して、無水硫酸ナトリウムで乾燥させて濃縮させ、カラムクロマトグラフィーをして、表題化合物であるＮ－（５－シアノ－４－（（（トランス）－２－メトキシシクロペンチル）アミノ）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミド（１５ｍｇ、７０％）を得た。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．５６ （ｓ, １Ｈ）, １０．２３ （ｓ, １Ｈ）, ８．１７ （ｓ, １Ｈ）, ７．７３ （ｓ, １Ｈ）, ７．６６ （ｓ, １Ｈ）, ５．１１（ｓ, ２Ｈ）, ４．８７ （ｍ, １Ｈ）, ４．２６ （ｓ, ２Ｈ）, ４．０９ （ｍ, ２Ｈ）, ３．９３－３．８５ （ｍ, ３Ｈ）, ３．６９ （ｍ, １Ｈ）, ３．４２－３．３９ （ｍ, ４Ｈ）, ２．９３ （ｍ, ２Ｈ）, ２．３３ （ｍ, １Ｈ）, ２．０７－２．０１（ｍ, ２Ｈ）, １．９５ － １．５０ （ｍ, ６Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５３４．１［Ｍ＋Ｈ］^＋． Example 1
N- (5-cyano-4-(((trans) -2-methoxycyclopentyl) amino) pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4-dihydro -1,8-Diazonaphthalene-1 (2H) -formamide

Step 1: N- (5-cyano-4-(((trans) -2-methoxycyclopentyl) amino) pyridine-2-yl) -7- (dimethoxymethyl) -6-((3-carbonylmorpholino) methyl) Production of -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

6-Amino-4-(((Trans) -2-methoxycyclopentyl) amino) nicotinonitrile (20 mg, 0.09 mmol), phenyl-7- (dimethoxymethyl) -6-((3-carbonylmorpholino) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -carboxylate (38 mg, 0.09 mmol) is mixed with THF (5 mL) and cooled to −78 ° C. in an _N2 atmosphere. , LiHMDS was added dropwise to a solution of LiHMDS in THF (0.2 mL, 0.2 mmol), the temperature was naturally raised to room temperature, and the reaction was carried out overnight. Saturated NH ₄ Cl aqueous solution (50 mL) is added, extracted with ethyl acetate (50 mL × 2), the organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatographed. , The title compound N- (5-cyano-4-(((trans) -2-methoxycyclopentyl) amino) pyridine-2-yl) -7- (dimethoxymethyl) -6-((3-carbonylmorpholino)) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide (23 mg, 46%) was obtained.
MS m / z (ESI): 580.2 [M + H] ⁺ .
Step 2: N- (5-cyano-4-(((trans) -2-methoxycyclopentyl) amino) pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3, Production of 4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

N- (5-cyano-4-(((trans) -2-methoxycyclopentyl) amino) pyridin-2-yl) -7- (dimethoxymethyl) -6-((3-carbonylmorpholino) methyl) -3, 4-Dihydro-1,8-diazonaphthalene-1 (2H) -formamide (23 mg, 0.04 mmol) was dissolved in THF / water (volume ratio: 11/4, 1.5 mL) and concentrated HCl (0. 15 mL (1.8 mmol) was added, and the mixture was reacted at room temperature for 2 hours. Saturated NaHCO ₃ aqueous solution (50 mL) was added, extracted with ethyl acetate (50 mL × 2), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatographed. The title compound N- (5-cyano-4-(((trans) -2-methoxycyclopentyl) amino) pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3 , 4-Dihydro-1,8-diazonaphthalene-1 (2H) -formamide (15 mg, 70%) was obtained.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.56 (s, 1H), 10.23 (s, 1H), 8.17 (s, 1H), 7.73 (s, 1H), 7.66 (S, 1H), 5.11 (s, 2H), 4.87 (m, 1H), 4.26 (s, 2H), 4.09 (m, 2H), 3.93-3.85 ( m, 3H), 3.69 (m, 1H), 3.42-3.39 (m, 4H), 2.93 (m, 2H), 2.33 (m, 1H), 2.07-2 0.01 (m, 2H), 1.95-1.50 (m, 6H);
MS m / z (ESI): 534.1 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（２－（ピロリジン－１－イル）エチル）アミノ）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．５６ （ｓ, １Ｈ）, １０．２３ （ｓ, １Ｈ）, ８．１７ （ｓ, １Ｈ）, ７．６７ （ｓ, １Ｈ）, ７．５３ （ｓ, １Ｈ）, ５．８３ （ｓ, １Ｈ）, ５．１１（ｓ, ２Ｈ）, ４．２６ （ｓ, ２Ｈ）, ４．１１－４．０５ （ｍ, ２Ｈ）, ３．９１－３．８６ （ｍ, ２Ｈ）, ３．４７－３．３８ （ｍ, ４Ｈ）, ２．９４ （ｍ, ２Ｈ）, ２．８７ （ｍ, ２Ｈ）, ２．６８ （ｍ, ４Ｈ）, ２．０８－２．０１（ｍ, ２Ｈ）, １．８６ （ｍ, ４Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５３３．２ ［Ｍ＋Ｈ］^＋． Example 2
N- (5-cyano-4-((2- (pyrrolidin-1-yl) ethyl) amino) pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4 -Dihydro-1,8-diazonaphthalene-1 (2H) -formamide

N- (5-cyano-4-((2- (pyrrolidin-1-yl) ethyl) amino) pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4 For the method for producing -dihydro-1,8-diazonaphthalene-1 (2H) -formamide, refer to Example 1.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.56 (s, 1H), 10.23 (s, 1H), 8.17 (s, 1H), 7.67 (s, 1H), 7.53 (S, 1H), 5.83 (s, 1H), 5.11 (s, 2H), 4.26 (s, 2H), 4.11-4.05 (m, 2H), 3.91- 3.86 (m, 2H), 3.47-3.38 (m, 4H), 2.94 (m, 2H), 2.87 (m, 2H), 2.68 (m, 4H), 2 .08-2.01 (m, 2H), 1.86 (m, 4H);
MS m / z (ESI): 533.2 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（２－メチルテトラヒドロフラン－３－イル）チオ）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．８３ （ｓ, １Ｈ）, １０．１６ （ｓ, １Ｈ）, ８．３０ （ｓ, １Ｈ）, ８．２５ （ｓ, １Ｈ）, ７．６２ （ｓ, １Ｈ）, ５．０４ （ｓ, ２Ｈ）, ４．３４ （ｍ, １Ｈ）, ４．１９ （ｓ, ２Ｈ）, ４．０６－３．９９ （ｍ, ４Ｈ）, ３．８０ （ｍ, ３Ｈ）, ３．３９－３．３２ （ｍ, ２Ｈ）, ２．８８ （ｍ, ２Ｈ）, ２．６０ （ｍ, １Ｈ）, ２．０９－１．９５ （ｍ, ３Ｈ）, １．２９ （ｄ, Ｊ ＝ ６．４ Ｈｚ, ３Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５３７．１［Ｍ＋Ｈ］^＋． Example 3
N- (5-cyano-4-((2-Methyltetrahydro-3-yl) thio) Pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4-dihydro -1,8-Diazonaphthalene-1 (2H) -formamide

N- (5-cyano-4-((2-Methyltetrahydro-3-yl) thio) Pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4-dihydro Example 1 may be referred to for the method for producing -1,8-diazonaphthalene-1 (2H) -formamide.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.83 (s, 1H), 10.16 (s, 1H), 8.30 (s, 1H), 8.25 (s, 1H), 7.62 (S, 1H), 5.04 (s, 2H), 4.34 (m, 1H), 4.19 (s, 2H), 4.06-3.99 (m, 4H), 3.80 ( m, 3H), 3.39-3.32 (m, 2H), 2.88 (m, 2H), 2.60 (m, 1H), 2.09-1.95 (m, 3H), 1 .29 (d, J = 6.4 Hz, 3H);
MS m / z (ESI): 537.1 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（３－メトキシピロリジン－１－イル）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．５０ （ｓ, １Ｈ）, １０．２３ （ｓ, １Ｈ）, ８．２０ （ｓ, １Ｈ）, ７．６６ （ｓ, １Ｈ）, ７．４８ （ｓ, １Ｈ）, ５．１１（ｓ, ２Ｈ）, ４．２５ （ｓ, ２Ｈ）, ４．０８ （ｍ, ３Ｈ）, ３．９１－３．８７ （ｍ, ２Ｈ）, ３．８０ （ｍ, ４Ｈ）, ３．４３－３．３９ （ｍ, ２Ｈ）, ３．３７ （ｓ, ３Ｈ）, ２．９３ （ｍ, ２Ｈ）, ２．２６－２．１９ （ｍ, １Ｈ）, ２．０８－２．０１（ｍ, ３Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５２０．２ ［Ｍ＋Ｈ］^＋． Example 4
N- (5-Cyano-4- (3-methoxypyrrolidin-1-yl) pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4-dihydro-1, 8-Diazonaphthalene-1 (2H) -formamide

N- (5-Cyano-4- (3-methoxypyrrolidin-1-yl) pyridin-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4-dihydro-1, Example 1 may be referred to for the method for producing 8-diazonaphthalene-1 (2H) -formamide.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.50 (s, 1H), 10.23 (s, 1H), 8.20 (s, 1H), 7.66 (s, 1H), 7.48 (S, 1H), 5.11 (s, 2H), 4.25 (s, 2H), 4.08 (m, 3H), 3.91-3.87 (m, 2H), 3.80 ( m, 4H), 3.43-3.39 (m, 2H), 3.37 (s, 3H), 2.93 (m, 2H), 2.26-2.19 (m, 1H), 2 .08-2.01 (m, 3H);
MS m / z (ESI): 520.2 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（２－（シクロペントキシ）エチル）アミノ）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．５６ （ｓ, １Ｈ）, １０．２３ （ｓ, １Ｈ）, ８．１７ （ｓ, １Ｈ）, ７．６６ （ｓ, １Ｈ）, ７．５５ （ｓ, １Ｈ）, ５．３５ （ｍ, １Ｈ）, ５．１１（ｓ, ２Ｈ）, ４．２６ （ｓ, ２Ｈ）, ４．１１－４．０６ （ｍ, ２Ｈ）, ３．９５ （ｍ, １Ｈ）, ３．９１－３．８６ （ｍ, ２Ｈ）, ３．６４ （ｍ, ２Ｈ）, ３．４８－３．３９ （ｍ, ４Ｈ）, ２．９４ （ｍ, ２Ｈ）, ２．０４ （ｍ, ２Ｈ）, １．７１（ｍ, ６Ｈ）, １．５６ （ｍ, ２Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５４８．２ ［Ｍ＋Ｈ］^＋． Example 5
N- (5-Cyano-4-((2- (cyclopentoxy) ethyl) amino) Pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4-dihydro -1,8-Diazonaphthalene-1 (2H) -formamide

N- (5-Cyano-4-((2- (cyclopentoxy) ethyl) amino) Pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4-dihydro Example 1 may be referred to for the method for producing -1,8-diazonaphthalene-1 (2H) -formamide.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.56 (s, 1H), 10.23 (s, 1H), 8.17 (s, 1H), 7.66 (s, 1H), 7.55 (S, 1H), 5.35 (m, 1H), 5.11 (s, 2H), 4.26 (s, 2H), 4.11-4.06 (m, 2H), 3.95 ( m, 1H), 3.91-3.86 (m, 2H), 3.64 (m, 2H), 3.48-3.39 (m, 4H), 2.94 (m, 2H), 2 .04 (m, 2H), 1.71 (m, 6H), 1.56 (m, 2H);
MS m / z (ESI): 548.2 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（２－メトキシエチル）アミノ）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニル－１,４－オキサゼパン－４－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．５３ （ｓ, １Ｈ）, １０．１６ （ｓ, １Ｈ）, ８．１１（ｓ, １Ｈ）, ７．５７ （ｓ, １Ｈ）, ７．５０ （ｓ, １Ｈ）, ５．０１（ｓ, ２Ｈ）, ４．２５ （ｓ, ２Ｈ）, ４．０４ － ３．９８ （ｍ, ２Ｈ）, ３．７８ （ｍ, ２Ｈ）, ３．５７ （ｍ, ２Ｈ）, ３．４９－３．４５ （ｍ, ２Ｈ）, ３．４２ （ｍ, ２Ｈ）, ３．３４ （ｓ, ３Ｈ）, ３．２０ （ｓ, １Ｈ）, ２．８６ （ｍ, ２Ｈ）, １．９６ （ｍ, ２Ｈ）, １．８４ （ｍ, ２Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５０８．１［Ｍ＋Ｈ］^＋． Example 6
N- (5-Cyano-4-((2-methoxyethyl) amino) Pyridine-2-yl) -7-formyl-6-((3-carbonyl-1,4-oxazepan-4-yl) methyl)- 3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

N- (5-Cyano-4-((2-methoxyethyl) amino) Pyridine-2-yl) -7-formyl-6-((3-carbonyl-1,4-oxazepan-4-yl) methyl)- Example 1 may be referred to for a method for producing 3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.53 (s, 1H), 10.16 (s, 1H), 8.11 (s, 1H), 7.57 (s, 1H), 7.50 (S, 1H), 5.01 (s, 2H), 4.25 (s, 2H), 4.04-3.98 (m, 2H), 3.78 (m, 2H), 3.57 ( m, 2H), 3.49-3.45 (m, 2H), 3.42 (m, 2H), 3.34 (s, 3H), 3.20 (s, 1H), 2.86 (m) , 2H), 1.96 (m, 2H), 1.84 (m, 2H);
MS m / z (ESI): 508.1 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（２－メトキシエチル）アミノ）ピリジン－２－イル）－７－ホルミル－６－（（４－メチル－２－カルボニル－１,４－ジアゼパン－１－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．５５ （ｓ, １Ｈ）, １０．１６ （ｓ, １Ｈ）, ８．１１（ｓ, １Ｈ）, ７．６０ （ｓ, １Ｈ）, ７．５０ （ｓ, １Ｈ）, ４．９８ （ｓ, ２Ｈ）, ４．００ （ｍ, ２Ｈ）, ３．５７ （ｍ, ２Ｈ）, ３．４５－３．３６ （ｍ, ６Ｈ）, ３．３４ （ｓ, ３Ｈ）, ３．２０ （ｓ, １Ｈ）, ２．８５ （ｍ, ２Ｈ）, ２．８１－２．７５ （ｍ, ２Ｈ）, ２．３７ （ｓ, ３Ｈ）, １．９８－１．９３ （ｍ, ２Ｈ）, １．６９－１．６５ （ｍ, ２Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５２１．２ ［Ｍ＋Ｈ］^＋． Example 7
N- (5-cyano-4-((2-Methoxyethyl) amino) pyridin-2-yl) -7-formyl-6-((4-methyl-2-carbonyl-1,4-diazepan-1-yl) ) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

N- (5-cyano-4-((2-Methoxyethyl) amino) pyridin-2-yl) -7-formyl-6-((4-methyl-2-carbonyl-1,4-diazepan-1-yl) ) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide may be produced by referring to Example 1.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.55 (s, 1H), 10.16 (s, 1H), 8.11 (s, 1H), 7.60 (s, 1H), 7.50 (S, 1H), 4.98 (s, 2H), 4.00 (m, 2H), 3.57 (m, 2H), 3.45-3.36 (m, 6H), 3.34 ( s, 3H), 3.20 (s, 1H), 2.85 (m, 2H), 2.81-2.75 (m, 2H), 2.37 (s, 3H), 1.98-1 .93 (m, 2H), 1.69-1.65 (m, 2H);
MS m / z (ESI): 521.2 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（２－メトキシフェニル）アミノ）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．６２ （ｓ, １Ｈ）, １０．２３ （ｓ, １Ｈ）, ８．３０ （ｓ, １Ｈ）, ８．０６ （ｓ, １Ｈ）, ７．６５ （ｓ, １Ｈ）, ７．５０ （ｍ, １Ｈ）, ７．１７ （ｍ, １Ｈ）, ７．０７ （ｍ, １Ｈ）, ６．９８ （ｍ, １Ｈ）, ６．９０ （ｓ, １Ｈ）, ５．１０ （ｓ, ２Ｈ）, ４．２５ （ｓ, ２Ｈ）, ４．０８－４．００ （ｍ, ２Ｈ）, ３．８８ （ｍ, ５Ｈ）, ３．４４－３．３７ （ｍ, ２Ｈ）, ２．９１（ｍ, ２Ｈ）, ２．０４－１．９６ （ｍ, ２Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５４２．０ ［Ｍ＋Ｈ］^＋． Example 8
N- (5-Cyano-4-((2-methoxyphenyl) amino) Pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4-dihydro-1,8 -Diazonaphthalene-1 (2H) -formamide

N- (5-Cyano-4-((2-methoxyphenyl) amino) Pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4-dihydro-1,8 Example 1 may be referred to for the method for producing -diazonaphthalene-1 (2H) -formamide.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.62 (s, 1H), 10.23 (s, 1H), 8.30 (s, 1H), 8.06 (s, 1H), 7.65 (S, 1H), 7.50 (m, 1H), 7.17 (m, 1H), 7.07 (m, 1H), 6.98 (m, 1H), 6.90 (s, 1H) , 5.10 (s, 2H), 4.25 (s, 2H), 4.08-4.00 (m, 2H), 3.88 (m, 5H), 3.44-3.37 (m) , 2H), 2.91 (m, 2H), 2.04-1.96 (m, 2H);
MS m / z (ESI): 542.0 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（（１－メトキシシクロプロピル）メチル）アミノ）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．５８ （ｓ, １Ｈ）, １０．２７ （ｓ, １Ｈ）, ８．２０ （ｓ, １Ｈ）, ７．６８ （ｓ, １Ｈ）, ７．５８ （ｓ, １Ｈ）, ５．４５ （ｓ, １Ｈ）, ５．１２ （ｓ, ２Ｈ）, ４．２５ （ｓ, ２Ｈ）, ４．１７－４．０３ （ｍ, ２Ｈ）, ４．００－３．８０ （ｍ, ２Ｈ）, ３．４２ （ｔ, Ｊ ＝ ５．０ Ｈｚ, ４Ｈ）, ３．３１（ｓ, ３Ｈ）, ２．９４ （ｔ, Ｊ ＝ ６．２ Ｈｚ, ２Ｈ）, ２．１５－１．９９ （ｍ, ２Ｈ）, ０．９７ （ｍ, ２Ｈ）, ０．６４ （ｍ, ２Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５２０．２ ［Ｍ＋Ｈ］^＋． Example 9
N- (5-Cyano-4-(((1-methoxycyclopropyl) methyl) amino) Pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4-dihydro -1,8-Diazonaphthalene-1 (2H) -formamide

N- (5-Cyano-4-(((1-methoxycyclopropyl) methyl) amino) Pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4-dihydro Example 1 may be referred to for the method for producing -1,8-diazonaphthalene-1 (2H) -formamide.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.58 (s, 1H), 10.27 (s, 1H), 8.20 (s, 1H), 7.68 (s, 1H), 7.58 (S, 1H), 5.45 (s, 1H), 5.12 (s, 2H), 4.25 (s, 2H), 4.17-4.03 (m, 2H), 4.00- 3.80 (m, 2H), 3.42 (t, J = 5.0 Hz, 4H), 3.31 (s, 3H), 2.94 (t, J = 6.2 Hz, 2H), 2.15-1.99 (m, 2H), 0.97 (m, 2H), 0.64 (m, 2H);
MS m / z (ESI): 520.2 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（２－シクロプロポキシエチル）アミノ）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
ＭＳ ｍ／ｚ （ＥＳＩ）： ５２０．２ ［Ｍ＋Ｈ］^＋． Example 10
N- (5-Cyano-4-((2-cyclopropoxyethyl) amino) Pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4-dihydro-1, 8-Diazonaphthalene-1 (2H) -formamide

N- (5-Cyano-4-((2-cyclopropoxyethyl) amino) Pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4-dihydro-1, Example 1 may be referred to for the method for producing 8-diazonaphthalene-1 (2H) -formamide.
MS m / z (ESI): 520.2 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（１－（メトキシメチル）シクロプロピル）アミノ）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．５３ （ｓ, １Ｈ）, １０．１８ （ｓ, １Ｈ）, ８．１２ （ｓ, １Ｈ）, ７．８４ （ｓ, １Ｈ）, ７．６０ （ｓ, １Ｈ）, ５．５９ （ｓ, １Ｈ）, ５．０４ （ｓ, ２Ｈ）, ４．１９ （ｓ, ２Ｈ）, ４．０３ （ｍ, ２Ｈ）, ３．８２（ｍ, ２Ｈ）, ３．４１（ｄ, Ｊ ＝ ６．７ Ｈｚ, ２Ｈ）, ３．３５ （ｍ, ２Ｈ）, ３．２８ （ｓ, ３Ｈ）, ２．８７ （ｔ, Ｊ ＝ ６．１Ｈｚ, ２Ｈ）, １．９８ （ｍ, ２Ｈ）, ０．９８ （ｍ, ２Ｈ）, ０．９１（ｍ, ２Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５２０．２ ［Ｍ＋Ｈ］^＋． Example 11
N- (5-Cyano-4-((1- (methoxymethyl) cyclopropyl) amino) Pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4-dihydro -1,8-Diazonaphthalene-1 (2H) -formamide

N- (5-Cyano-4-((1- (methoxymethyl) cyclopropyl) amino) Pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4-dihydro Example 1 may be referred to for the method for producing -1,8-diazonaphthalene-1 (2H) -formamide.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.53 (s, 1H), 10.18 (s, 1H), 8.12 (s, 1H), 7.84 (s, 1H), 7.60 (S, 1H), 5.59 (s, 1H), 5.04 (s, 2H), 4.19 (s, 2H), 4.03 (m, 2H), 3.82 (m, 2H) , 3.41 (d, J = 6.7 Hz, 2H), 3.35 (m, 2H), 3.28 (s, 3H), 2.87 (t, J = 6.1 Hz, 2H), 1.98 (m, 2H), 0.98 (m, 2H), 0.91 (m, 2H);
MS m / z (ESI): 520.2 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（２－（シクロプロピルメトキシ）エチル）アミノ）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
ＭＳ ｍ／ｚ （ＥＳＩ）： ５３４．２ ［Ｍ＋Ｈ］^＋． Example 12
N- (5-Cyano-4-((2- (cyclopropylmethoxy) ethyl) amino) Pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4-dihydro -1,8-Diazonaphthalene-1 (2H) -formamide

N- (5-Cyano-4-((2- (cyclopropylmethoxy) ethyl) amino) Pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4-dihydro Example 1 may be referred to for the method for producing -1,8-diazonaphthalene-1 (2H) -formamide.
MS m / z (ESI): 534.2 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（２－メトキシエチル）チオ）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．８７ （ｓ, １Ｈ）, １０．２３ （ｓ, １Ｈ）, ８．３５ （ｓ, １Ｈ）, ８．２７ （ｓ, １Ｈ）, ７．６９ （ｓ, １Ｈ）, ５．１１（ｓ, ２Ｈ）, ４．２６ （ｓ, ２Ｈ）, ４．１１－４．０８ （ｍ, ２Ｈ）, ３．９１－３．８８ （ｍ, ２Ｈ）, ３．７７－３．７４ （ｍ, ２Ｈ）, ３．４６－３．３９ （ｍ, ５Ｈ）, ３．３６－３．３２ （ｍ, ２Ｈ）, ２．９３ （ｔ, Ｊ ＝ ６．２ Ｈｚ, ２Ｈ）, ２．１０－２．０２ （ｍ, ２Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５１１．１［Ｍ＋Ｈ］^＋． Example 13
N- (5-cyano-4-((2-methoxyethyl) thio) pyridin-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4-dihydro-1,8 -Diazonaphthalene-1 (2H) -formamide

N- (5-cyano-4-((2-methoxyethyl) thio) pyridin-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4-dihydro-1,8 Example 1 may be referred to for a method for producing -diazonaphthalene-1 (2H) -formamide.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.87 (s, 1H), 10.23 (s, 1H), 8.35 (s, 1H), 8.27 (s, 1H), 7.69 (S, 1H), 5.11 (s, 2H), 4.26 (s, 2H), 4.11-4.08 (m, 2H), 3.91-3.88 (m, 2H), 3.77-3.74 (m, 2H), 3.46-3.39 (m, 5H), 3.36-3.32 (m, 2H), 2.93 (t, J = 6.2) Hz, 2H), 2.10-2.02 (m, 2H);
MS m / z (ESI): 511.1 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（テトラヒドロフラン－３－イル）チオ）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．９０ （ｓ, １Ｈ）, １０．２３ （ｓ, １Ｈ）, ８．３７ （ｓ, １Ｈ）, ８．２８ （ｓ, １Ｈ）, ７．６９ （ｓ, １Ｈ）, ５．１１（ｓ, ２Ｈ）, ４．４０－４．３２ （ｍ, １Ｈ）, ４．２６ （ｓ, ２Ｈ）, ４．１３－４．０６ （ｍ, ３Ｈ）, ４．０２－３．９６ （ｍ, ２Ｈ）, ３．９４－３．８６ （ｍ, ２Ｈ）, ３．８４－３．７６ （ｍ, １Ｈ）, ３．４５－３．４０ （ｍ, ２Ｈ）, ２．９５ （ｔ, Ｊ ＝ ６．２ Ｈｚ, ２Ｈ）, ２．６４－２．５５ （ｍ, １Ｈ）, ２．１０－２．０２ （ｍ, ３Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５２３．１［Ｍ＋Ｈ］^＋． Example 14
N- (5-cyano-4-((tetrahydro-3-yl) thio) pyridin-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4-dihydro-1, 8-Diazonaphthalene-1 (2H) -formamide

N- (5-cyano-4-((tetrahydro-3-yl) thio) pyridin-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4-dihydro-1, Example 1 may be referred to for the method for producing 8-diazonaphthalene-1 (2H) -formamide.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.90 (s, 1H), 10.23 (s, 1H), 8.37 (s, 1H), 8.28 (s, 1H), 7.69 (S, 1H), 5.11 (s, 2H), 4.40-4.32 (m, 1H), 4.26 (s, 2H), 4.13-4.06 (m, 3H), 4.02-3.96 (m, 2H), 3.94-3.86 (m, 2H), 3.84-3.76 (m, 1H), 3.45-3.40 (m, 2H) ), 2.95 (t, J = 6.2 Hz, 2H), 2.64-2.55 (m, 1H), 2.10-2.02 (m, 3H);
MS m / z (ESI): 523.1 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（（シス）－２－メトキシシクロペンチル）アミノ）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３）： δ １３．５３ （ｓ, １Ｈ）, １０．２４ （ｓ, １Ｈ）, ８．１６ （ｓ, １Ｈ）, ７．６７ （ｓ, １Ｈ）, ７．５６ （ｓ, １Ｈ）, ５．８７ （ｓ, １Ｈ）, ５．１１（ｓ, ２Ｈ）, ４．２５ （ｓ, ２Ｈ）, ４．０８ （ｍ, ２Ｈ）, ３．８８ （ｍ, ３Ｈ）, ３．８６－３．７９ （ｍ, １Ｈ）, ３．４５ （ｍ, ２Ｈ）, ３．３８ （ｓ, ３Ｈ）, ２．９３ （ｔ, Ｊ ＝ ６．２ Ｈｚ, ２Ｈ）, ２．３０－２．１８ （ｍ, １Ｈ）, ２．１０－２．００ （ｍ, ２Ｈ）, １．９４－１．７７ （ｍ, ３Ｈ）, １．６５ （ｍ, ２Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５３４．２ ［Ｍ＋Ｈ］^＋． Example 15
N- (5-cyano-4-(((cis) -2-methoxycyclopentyl) amino) pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4-dihydro -1,8-Diazonaphthalene-1 (2H) -formamide

N- (5-cyano-4-(((cis) -2-methoxycyclopentyl) amino) pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4-dihydro Example 1 may be referred to for the method for producing -1,8-diazonaphthalene-1 (2H) -formamide.
^{1 1} H NMR (400 MHz, CDCl ₃ ): δ 13.53 (s, 1H), 10.24 (s, 1H), 8.16 (s, 1H), 7.67 (s, 1H), 7. 56 (s, 1H), 5.87 (s, 1H), 5.11 (s, 2H), 4.25 (s, 2H), 4.08 (m, 2H), 3.88 (m, 3H) ), 3.86-3.79 (m, 1H), 3.45 (m, 2H), 3.38 (s, 3H), 2.93 (t, J = 6.2 Hz, 2H), 2 .30-2.18 (m, 1H), 2.10-2.00 (m, 2H), 1.94-1.77 (m, 3H), 1.65 (m, 2H);
MS m / z (ESI): 534.2 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（（トランス）－２－メトキシシクロペンチル）オキソ）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３）： δ １３．８１（ｓ, １Ｈ）, １０．２４ （ｓ, １Ｈ）, ８．３５ （ｓ, １Ｈ）, ８．０５ （ｓ, １Ｈ）, ７．６８ （ｓ, １Ｈ）, ５．１１（ｓ, ２Ｈ）, ４．８９－４．８１（ｍ, １Ｈ）, ４．２６ （ｓ, ２Ｈ）, ４．１０ （ｍ, ２Ｈ）, ４．０１－３．９４ （ｍ, １Ｈ）, ３．９３－３．８５ （ｍ, ２Ｈ）, ３．４７－３．３８ （ｍ, ５Ｈ）, ２．９５ （ｔ, Ｊ ＝ ６．２ Ｈｚ, ２Ｈ）, ２．３０－２．２０ （ｍ, １Ｈ）, ２．０５ （ｍ, ３Ｈ）, １．８３ （ｍ, ３Ｈ）, １．７７－１．７０ （ｍ, １Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５３５．２ ［Ｍ＋Ｈ］^＋． Example 16
N- (5-cyano-4-(((trans) -2-methoxycyclopentyl) oxo) pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4-dihydro -1,8-Diazonaphthalene-1 (2H) -formamide

N- (5-cyano-4-(((trans) -2-methoxycyclopentyl) oxo) pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4-dihydro Example 1 may be referred to for the method for producing -1,8-diazonaphthalene-1 (2H) -formamide.
^{1 1} H NMR (400 MHz, CDCl ₃ ): δ 13.81 (s, 1H), 10.24 (s, 1H), 8.35 (s, 1H), 8.05 (s, 1H), 7. 68 (s, 1H), 5.11 (s, 2H), 4.89-4.81 (m, 1H), 4.26 (s, 2H), 4.10 (m, 2H), 4.01 -3.94 (m, 1H), 3.93-3.85 (m, 2H), 3.47-3.38 (m, 5H), 2.95 (t, J = 6.2 Hz, 2H) ), 2.30-2.20 (m, 1H), 2.05 (m, 3H), 1.83 (m, 3H), 1.77-1.70 (m, 1H);
MS m / z (ESI): 535.2 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（１－メトキシシクロプロピル）メトキシ基）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
ＭＳ ｍ／ｚ （ＥＳＩ）： ５２１．２ ［Ｍ＋Ｈ］^＋． Example 17
N- (5-cyano-4-((1-methoxycyclopropyl) methoxy group) pyridin-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4-dihydro-1 , 8-Diazonaphthalene-1 (2H) -formamide

N- (5-cyano-4-((1-methoxycyclopropyl) methoxy group) pyridin-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4-dihydro-1 For the method for producing, 8-diazonaphthalene-1 (2H) -formamide, Example 1 may be referred to.
MS m / z (ESI): 521.2 [M + H] ⁺ .

Ｎ－（５－シアノ－３－フルオロ－４－（（２－メトキシエチル）アミノ）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
ＭＳ ｍ／ｚ （ＥＳＩ）： ５１２．２ ［Ｍ＋Ｈ］^＋． Example 18
N- (5-Cyano-3-fluoro-4-((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4-dihydro -1,8-Diazonaphthalene-1 (2H) -formamide

N- (5-Cyano-3-fluoro-4-((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4-dihydro Example 1 may be referred to for the method for producing -1,8-diazonaphthalene-1 (2H) -formamide.
MS m / z (ESI): 512.2 [M + H] ⁺ .

７－ホルミル－Ｎ－（４－（（２－メトキシエチル）アミノ）－５－シアノチオピリジン－２－イル）－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
ＭＳ ｍ／ｚ （ＥＳＩ）： ５２６．１［Ｍ＋Ｈ］^＋． Example 19
7-formyl-N- (4-((2-methoxyethyl) amino) -5-cyanothiopyridine-2-yl) -6-((3-carbonylmorpholino) methyl) -3,4-dihydro-1, 8-Diazonaphthalene-1 (2H) -formamide

7-formyl-N- (4-((2-methoxyethyl) amino) -5-cyanothiopyridine-2-yl) -6-((3-carbonylmorpholino) methyl) -3,4-dihydro-1, Example 1 may be referred to for the method for producing 8-diazonaphthalene-1 (2H) -formamide.
MS m / z (ESI): 526.1 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（２－メトキシエチル）アミノ）ピリジン－２－イル）－７－ホルミル－６－（（６－カルボニル－４－オキサ－７－アザスピロ［２．５］オクタン－７－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
ＭＳ ｍ／ｚ （ＥＳＩ）： ５２０．２ ［Ｍ＋Ｈ］^＋． Example 20
N- (5-cyano-4-((2-Methoxyethyl) amino) pyridin-2-yl) -7-formyl-6-((6-carbonyl-4-oxa-7-azaspiro [2.5] octane) -7-Il) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

N- (5-cyano-4-((2-Methoxyethyl) amino) pyridin-2-yl) -7-formyl-6-((6-carbonyl-4-oxa-7-azaspiro [2.5] octane) Example 1 may be referred to for the method for producing -7-yl) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide.
MS m / z (ESI): 520.2 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（２－メトキシエチル）アミノ）ピリジン－２－イル）－７－ホルミル－６－（（５－カルボニル－７－オキサ－４－アザスピロ［２．５］オクタン－４－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．５３ （ｓ, １Ｈ）, １０．２２ （ｓ, １Ｈ）, ８．１７ （ｓ, １Ｈ）, ７．５６ （ｓ, １Ｈ）, ７．４２ （ｓ, １Ｈ）, ４．８６ （ｓ, ２Ｈ）, ４．４７ （ｓ, ２Ｈ）, ４．１０－４．０７（ｍ, ２Ｈ）, ３．７５ （ｓ, ２Ｈ）, ３．６５－３．６２ （ｍ, ２Ｈ）, ３．５１－３．４７ （ｍ, ２Ｈ）, ３．４１（ｓ, ３Ｈ）, ２．９４ （ｔ, Ｊ ＝ ６．２ Ｈｚ, ２Ｈ）, ２．０８－２．０２ （ｍ, ２Ｈ）, ０．９３－０．９０ （ｍ, ２Ｈ）, ０．７３－０．７０ （ｍ, ２Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５２０．２ ［Ｍ＋Ｈ］^＋． Example 21
N- (5-cyano-4-((2-Methoxyethyl) amino) pyridin-2-yl) -7-formyl-6-((5-carbonyl-7-oxa-4-azaspiro [2.5] octane) -4-yl) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

N- (5-cyano-4-((2-Methoxyethyl) amino) pyridin-2-yl) -7-formyl-6-((5-carbonyl-7-oxa-4-azaspiro [2.5] octane) Example 1 may be referred to for the method for producing -4-yl) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.53 (s, 1H), 10.22 (s, 1H), 8.17 (s, 1H), 7.56 (s, 1H), 7.42 (S, 1H), 4.86 (s, 2H), 4.47 (s, 2H), 4.10-4.07 (m, 2H), 3.75 (s, 2H), 3.65- 3.62 (m, 2H), 3.51-3.47 (m, 2H), 3.41 (s, 3H), 2.94 (t, J = 6.2 Hz, 2H), 2.08 -2.02 (m, 2H), 0.93-0.90 (m, 2H), 0.73-0.70 (m, 2H);
MS m / z (ESI): 520.2 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（２－メトキシエチル）アミノ）ピリジン－２－イル）－７－ホルミル－６－（（８－カルボニル－４－オキサ－７－アザスピロ［２．５］オクタン－７－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
ＭＳ ｍ／ｚ （ＥＳＩ）： ５２０．２ ［Ｍ＋Ｈ］^＋． Example 22
N- (5-cyano-4-((2-Methoxyethyl) amino) pyridin-2-yl) -7-formyl-6-((8-carbonyl-4-oxa-7-azaspiro [2.5] octane) -7-Il) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

N- (5-cyano-4-((2-Methoxyethyl) amino) pyridin-2-yl) -7-formyl-6-((8-carbonyl-4-oxa-7-azaspiro [2.5] octane) Example 1 may be referred to for the method for producing -7-yl) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide.
MS m / z (ESI): 520.2 [M + H] ⁺ .

ステップ１：Ｎ－（５－シアノ－４－（（２－メトキシエチル）アミノ）ピリジン－２－イル）－７－（ジメトキシメチル）－６－（（２－カルボニル－１,３－オキサゼパン－３－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの合成

Ｎ－（５－シアノ－４－（（２－メトキシエチル）アミノ）ピリジン－２－イル）－７－（ジメトキシメチル）－６－（（２－カルボニル－１,３－オキサゼパン－３－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造は実施例１のステップ１と同様である。
ＭＳ ｍ／ｚ （ＥＳＩ）： ５５４．２ ［Ｍ＋Ｈ］^＋．
ステップ２：Ｎ－（５－シアノ－４－（（２－メトキシエチル）アミノ）ピリジン－２－イル）－７－ホルミル－６－（（２－カルボニル－１,３－オキサゼパン－３－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの合成

Ｎ－（５－シアノ－４－（（２－メトキシエチル）アミノ）ピリジン－２－イル）－７－ホルミル－６－（（２－カルボニル－１,３－オキサゼパン－３－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造は実施例１のステップ２と同様である。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．６０ （ｓ, １Ｈ）, １０．２５ （ｓ, １Ｈ）, ８．１８ （ｓ, １Ｈ）, ７．７１（ｓ, １Ｈ）, ７．５９ （ｓ, １Ｈ）, ５．３７ （ｓ, １Ｈ）, ４．９５ （ｓ, ２Ｈ）, ４．１６－４．１４ （ｍ, ２Ｈ）, ４．０９－４．０６ （ｍ, ２Ｈ）, ３．６６－３．６３ （ｍ, ２Ｈ）, ３．５２－３．４８ （ｍ, ２Ｈ）, ３．４２ （ｓ, ３Ｈ）, ３．３２－３．２９ （ｍ, ２Ｈ）, ２．９４ （ｔ, Ｊ ＝ ６．３ Ｈｚ, ２Ｈ）, ２．１０－１．９６ （ｍ, ２Ｈ）, １．９５－１．８３ （ｍ, ２Ｈ）, １．７７－１．６９ （ｍ, ２Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５０８．２ ［Ｍ＋Ｈ］^＋． Example 23
N- (5-cyano-4-((2-Methoxyethyl) amino) pyridin-2-yl) -7-formyl-6-((2-carbonyl-1,3-oxazepan-3-yl) methyl)- 3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

Step 1: N- (5-Cyano-4-((2-methoxyethyl) amino) Pyridine-2-yl) -7- (dimethoxymethyl) -6-((2-carbonyl-1,3-oxazepan-3) -Synthesis of -yl) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

N- (5-Cyano-4-((2-methoxyethyl) amino) Pyridine-2-yl) -7- (dimethoxymethyl) -6-((2-carbonyl-1,3-oxazepan-3-yl)) The production of methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide is the same as in step 1 of Example 1.
MS m / z (ESI): 554.2 [M + H] ⁺ .
Step 2: N- (5-cyano-4-((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6-((2-carbonyl-1,3-oxazepan-3-yl)) Synthesis of methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

N- (5-cyano-4-((2-Methoxyethyl) amino) pyridin-2-yl) -7-formyl-6-((2-carbonyl-1,3-oxazepan-3-yl) methyl)- The production of 3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide is the same as in step 2 of Example 1.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.60 (s, 1H), 10.25 (s, 1H), 8.18 (s, 1H), 7.71 (s, 1H), 7.59 (S, 1H), 5.37 (s, 1H), 4.95 (s, 2H), 4.16-4.14 (m, 2H), 4.09-4.06 (m, 2H), 3.66-3.63 (m, 2H), 3.52-3.48 (m, 2H), 3.42 (s, 3H), 3.32-3.29 (m, 2H), 2. 94 (t, J = 6.3 Hz, 2H), 2.10-1.96 (m, 2H), 1.95-1.83 (m, 2H), 1.77-1.69 (m, 2H);
MS m / z (ESI): 508.2 [M + H] ⁺ .

（Ｓ）－Ｎ－（５－シアノ－４－（（（１－メトキシシクロプロピル）メチル）アミノ）ピリジン－２－イル）－７－ホルミル－６－（（４－メチル－２－カルボニルオキサゾリジン－３－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
ＭＳ ｍ／ｚ （ＥＳＩ）： ５２０．２ ［Ｍ＋Ｈ］^＋． Example 24
(S) -N- (5-Cyano-4-(((1-methoxycyclopropyl) methyl) amino) Pyridine-2-yl) -7-formyl-6-((4-Methyl-2-carbonyloxazolidine-) 3-Il) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

(S) -N- (5-Cyano-4-(((1-methoxycyclopropyl) methyl) amino) Pyridine-2-yl) -7-formyl-6-((4-Methyl-2-carbonyloxazolidine-) Example 1 may be referred to for the method for producing 3-yl) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide.
MS m / z (ESI): 520.2 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（（１－メトキシシクロプロピル）メチル）アミノ）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニル－１,４－オキサゼパン－４－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
ＭＳ ｍ／ｚ （ＥＳＩ）： ５３４．２ ［Ｍ＋Ｈ］^＋． Example 25
N- (5-Cyano-4-(((1-methoxycyclopropyl) methyl) amino) Pyridine-2-yl) -7-formyl-6-((3-carbonyl-1,4-oxazepan-4-yl) ) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

N- (5-Cyano-4-(((1-methoxycyclopropyl) methyl) amino) Pyridine-2-yl) -7-formyl-6-((3-carbonyl-1,4-oxazepan-4-yl) ) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide may be produced by referring to Example 1.
MS m / z (ESI): 534.2 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（３－メトキシピロリジン－１－イル）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニル－１,４－オキサゼパン－４－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
ＭＳ ｍ／ｚ （ＥＳＩ）： ５３４．２ ［Ｍ＋Ｈ］^＋． Example 26
N- (5-cyano-4- (3-methoxypyrrolidine-1-yl) pyridine-2-yl) -7-formyl-6-((3-carbonyl-1,4-oxazepan-4-yl) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

N- (5-cyano-4- (3-methoxypyrrolidine-1-yl) pyridin-2-yl) -7-formyl-6-((3-carbonyl-1,4-oxazepan-4-yl) methyl) Example 1 may be referred to for the method for producing -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide.
MS m / z (ESI): 534.2 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（（トランス）－２－メトキシシクロペンチル）アミノ）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニル－１,４－オキサゼパン－４－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
ＭＳ ｍ／ｚ （ＥＳＩ）： ５４８．２ ［Ｍ＋Ｈ］^＋． Example 27
N- (5-cyano-4-(((trans) -2-methoxycyclopentyl) amino) pyridine-2-yl) -7-formyl-6-((3-carbonyl-1,4-oxazepan-4-yl) ) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

N- (5-cyano-4-(((trans) -2-methoxycyclopentyl) amino) pyridine-2-yl) -7-formyl-6-((3-carbonyl-1,4-oxazepan-4-yl) ) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide may be produced by referring to Example 1.
MS m / z (ESI): 548.2 [M + H] ⁺ .

（Ｒ）－Ｎ－（５－シアノ－４－（（１－メトキシプロパン－２－イル）オキソ）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニル－１,４－オキサゼパン－４－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
ＭＳ ｍ／ｚ （ＥＳＩ）： ５２３．２ ［Ｍ＋Ｈ］^＋． Example 28
(R) -N- (5-cyano-4-((1-methoxypropan-2-yl) oxo) pyridine-2-yl) -7-formyl-6-((3-carbonyl-1,4-oxazepan) -4-yl) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

(R) -N- (5-cyano-4-((1-methoxypropan-2-yl) oxo) pyridine-2-yl) -7-formyl-6-((3-carbonyl-1,4-oxazepan) Example 1 may be referred to for the method for producing -4-yl) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide.
MS m / z (ESI): 523.2 [M + H] ⁺ .

ステップ１：（Ｒ）－Ｎ－（５－シアノ－４－（（１－メトキシプロパン－２－イル）アミノ）ピリジン－２－イル）－７－（ジメトキシメチル）－６－（（２－カルボニル－１,３－オキサゼパン－３－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの合成

（Ｒ）－６－アミノ－４－（（１－メトキシプロパン－２－イル）アミノ）ニコチノニトリル（３０ｍｇ、０．１４ｍｍｏｌ）、フェニル－７－（ジメトキシメチル）－６－（（２－カルボニル－１,３－オキサゼパン－３－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－カルボキシラート（６０ｍｇ、０．１３ｍｍｏｌ）をＴＨＦ（５ｍＬ）に溶解して、Ｎ_２雰囲気下で、－７８℃に冷却させ、ＬｉＨＭＤＳのＴＨＦ（０．３ｍＬ、０．３ｍｍｏｌ）溶液を反応液に滴下して、室温に自然昇温して一晩反応させた。飽和ＮＨ_４Ｃｌ水溶液（５０ｍＬ）を加えて、酢酸エチル（５０ｍＬ×２）で抽出し、有機相を合併して飽和食塩水で洗浄して、無水硫酸ナトリウムで乾燥させて濃縮させ、カラムクロマトグラフィーをして、表題化合物である（Ｒ）－Ｎ－（５－シアノ－４－（（１－メトキシプロパン－２－イル）アミノ）ピリジン－２－イル）－７－（ジメトキシメチル）－６－（（２－カルボニル－１,３－オキサゼパン－３－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミド（６５ｍｇ、８６％）を得た。
１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ３） δ １３．７０ （ｓ, １Ｈ）, ８．１８ （ｓ, １Ｈ）, ７．６０ （ｓ, ２Ｈ）, ５．４１（ｓ, １Ｈ）, ５．１２ （ｄ, Ｊ ＝ ７．８ Ｈｚ, １Ｈ）, ４．７３ （ｓ, ２Ｈ）, ４．２０－４．１１（ｍ, ２Ｈ）, ４．０６－３．９９ （ｍ, ２Ｈ）, ３．９３ （ｓ, １Ｈ）, ３．５２－３．４８ （ｍ, ７Ｈ）, ３．４６－３．４２ （ｍ, １Ｈ）, ３．３９ （ｓ, ３Ｈ）, ３．２６－３．２１（ｍ, ２Ｈ）, ２．８３ （ｔ, Ｊ ＝ ６．２ Ｈｚ, ２Ｈ）, ２．０３－１．９５ （ｍ, ２Ｈ）, １．９１－１．８３ （ｍ, ２Ｈ）, １．６７－１．６２ （ｍ, ２Ｈ）, １．３１（ｄ, Ｊ ＝ ６．６ Ｈｚ, ３Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５６８．３ ［Ｍ＋Ｈ］^＋．
ステップ２：（Ｒ）－Ｎ－（５－シアノ－４－（（１－メトキシプロパン－２－イル）アミノ）ピリジン－２－イル）－７－ホルミル－６－（（２－カルボニル－１,３－オキサゼパン－３－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの合成

（Ｒ）－Ｎ－（５－シアノ－４－（（１－メトキシプロパン－２－イル）アミノ）ピリジン－２－イル）－７－（ジメトキシメチル）－６－（（２－カルボニル－１,３－オキサゼパン－３－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミド（６５ｍｇ、０．１２ｍｍｏｌ）をＴＨＦ／水（体積比：１１／４、４．５ｍＬ）に溶解して、濃ＨＣｌ（０．４５ｍＬ、５．４ｍｍｏｌ）を加え、室温で２ｈ反応させた。飽和ＮａＨＣＯ_３水溶液（５０ｍＬ）を加えて、酢酸エチル（５０ｍＬ×２）で抽出し、有機相を合併して飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させて濃縮させ、カラムクロマトグラフィーをして、表題化合物である（Ｒ）－Ｎ－（５－シアノ－４－（（１－メトキシプロパン－２－イル）アミノ）ピリジン－２－イル）－７－ホルミル－６－（（２－カルボニル－１,３－オキサゼパン－３－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミド（３０ｍｇ、５１％）を得た。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．５７ （ｓ, １Ｈ）, １０．２６ （ｓ, １Ｈ）, ８．１７ （ｓ, １Ｈ）, ７．７１（ｓ, １Ｈ）, ７．６３ （ｓ, １Ｈ）, ５．２７ （ｓ, １Ｈ）, ４．９５ （ｓ, ２Ｈ）, ４．１９－４．１２ （ｍ, ２Ｈ）, ４．１１－４．０４ （ｍ, ２Ｈ）, ３．９４ （ｓ, １Ｈ）, ３．５２ （ｍ, １Ｈ）, ３．４８－３．３７ （ｍ, ４Ｈ）, ３．３３－３．２８ （ｍ, ２Ｈ）, ２．９３ （ｔ, Ｊ ＝ ６．３ Ｈｚ, ２Ｈ）, ２．０４ （ｍ, ２Ｈ）, １．９３－１．８５ （ｍ, ２Ｈ）, １．７３ （ｍ, ２Ｈ）, １．３９－１．２８ （ｍ, ３Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５２２．２ ［Ｍ＋Ｈ］^＋． Example 29
(R) -N- (5-cyano-4-((1-methoxypropan-2-yl) amino) pyridine-2-yl) -7-formyl-6-((2-carbonyl-1,3-oxazepan) -3-yl) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

Step 1: (R) -N- (5-cyano-4-((1-methoxypropan-2-yl) amino) pyridine-2-yl) -7- (dimethoxymethyl) -6-((2-carbonyl) Synthesis of -1,3-oxazepan-3-yl) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

(R) -6-amino-4-((1-methoxypropan-2-yl) amino) nicotinonitrile (30 mg, 0.14 mmol), phenyl-7- (dimethoxymethyl) -6-((2-carbonyl) -1,3-Oxazepan-3-yl) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -carboxylate (60 mg, 0.13 mmol) dissolved in THF (5 mL). , N ₂ atmosphere, cooled to −78 ° C., a solution of LiHMDS in THF (0.3 mL, 0.3 mmol) was added dropwise to the reaction solution, the temperature was naturally raised to room temperature, and the reaction was carried out overnight. Saturated NH ₄ Cl aqueous solution (50 mL) is added, extracted with ethyl acetate (50 mL × 2), combined with the organic phase, washed with saturated saline, dried over anhydrous sodium sulfate and concentrated, column chromatography. Then, the title compound (R) -N- (5-cyano-4-((1-methoxypropan-2-yl) amino) pyridine-2-yl) -7- (dimethoxymethyl) -6- ((2-carbonyl-1,3-oxazepan-3-yl) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide (65 mg, 86%) was obtained.
1H NMR (400 MHz, CDCl3) δ 13.70 (s, 1H), 8.18 (s, 1H), 7.60 (s, 2H), 5.41 (s, 1H), 5.12 (d) , J = 7.8 Hz, 1H), 4.73 (s, 2H), 4.20-4.11 (m, 2H), 4.06-3.99 (m, 2H), 3.93 ( s, 1H), 3.52-3.48 (m, 7H), 3.46-3.42 (m, 1H), 3.39 (s, 3H), 3.26-3.21 (m, 1H) 2H), 2.83 (t, J = 6.2 Hz, 2H), 2.03-1.95 (m, 2H), 1.91-1.83 (m, 2H), 1.67-1 .62 (m, 2H), 1.31 (d, J = 6.6 Hz, 3H);
MS m / z (ESI): 568.3 [M + H] ⁺ .
Step 2: (R) -N- (5-cyano-4-((1-methoxypropan-2-yl) amino) pyridin-2-yl) -7-formyl-6-((2-carbonyl-1,, Synthesis of 3-oxazepan-3-yl) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

(R) -N- (5-cyano-4-((1-methoxypropan-2-yl) amino) Pyridine-2-yl) -7- (dimethoxymethyl) -6-((2-carbonyl-1,, 3-Oxazepan-3-yl) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide (65 mg, 0.12 mmol) in THF / water (volume ratio: 11/4, 4) It was dissolved in (5.5 mL), concentrated HCl (0.45 mL, 5.4 mmol) was added, and the mixture was reacted at room temperature for 2 hours. Saturated NaHCO ₃ aqueous solution (50 mL) is added, extracted with ethyl acetate (50 mL × 2), combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatographed. The title compound (R) -N- (5-cyano-4-((1-methoxypropan-2-yl) amino) pyridine-2-yl) -7-formyl-6-((2-carbonyl) -1,3-Oxazepan-3-yl) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide (30 mg, 51%) was obtained.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.57 (s, 1H), 10.26 (s, 1H), 8.17 (s, 1H), 7.71 (s, 1H), 7.63 (S, 1H), 5.27 (s, 1H), 4.95 (s, 2H), 4.19-4.12 (m, 2H), 4.11-4.04 (m, 2H), 3.94 (s, 1H), 3.52 (m, 1H), 3.48-3.37 (m, 4H), 3.33-3.28 (m, 2H), 2.93 (t, J = 6.3 Hz, 2H), 2.04 (m, 2H), 1.93-1.85 (m, 2H), 1.73 (m, 2H), 1.39-1.28 (m) , 3H);
MS m / z (ESI): 522.2 [M + H] ⁺ .

（Ｓ）－Ｎ－（５－シアノ－４－（（１－メトキシプロパン－２－イル）アミノ）ピリジン－２－イル）－７－ホルミル－６－（（２－カルボニル－１,３－オキサゼパン－３－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例２９を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．５７ （ｓ, １Ｈ）, １０．２６ （ｓ, １Ｈ）, ８．１７ （ｓ, １Ｈ）, ７．７１（ｓ, １Ｈ）, ７．６３ （ｓ, １Ｈ）, ５．２７ （ｓ, １Ｈ）, ４．９５ （ｓ, ２Ｈ）, ４．１９－４．１２ （ｍ, ２Ｈ）, ４．１１－４．０４ （ｍ, ２Ｈ）, ３．９４ （ｓ, １Ｈ）, ３．５２ （ｍ, １Ｈ）, ３．４８－３．３７ （ｍ, ４Ｈ）, ３．３３－３．２８ （ｍ, ２Ｈ）, ２．９３ （ｔ, Ｊ ＝ ６．３ Ｈｚ, ２Ｈ）, ２．０４ （ｍ, ２Ｈ）, １．９３－１．８５ （ｍ, ２Ｈ）, １．７３ （ｍ, ２Ｈ）, １．３９－１．２８ （ｍ, ３Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５２２．２ ［Ｍ＋Ｈ］^＋． Example 30
(S) -N- (5-cyano-4-((1-methoxypropan-2-yl) amino) pyridine-2-yl) -7-formyl-6-((2-carbonyl-1,3-oxazepan) -3-yl) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

(S) -N- (5-cyano-4-((1-methoxypropan-2-yl) amino) pyridine-2-yl) -7-formyl-6-((2-carbonyl-1,3-oxazepan) For the method for producing -3-yl) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide, see Example 29.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.57 (s, 1H), 10.26 (s, 1H), 8.17 (s, 1H), 7.71 (s, 1H), 7.63 (S, 1H), 5.27 (s, 1H), 4.95 (s, 2H), 4.19-4.12 (m, 2H), 4.11-4.04 (m, 2H), 3.94 (s, 1H), 3.52 (m, 1H), 3.48-3.37 (m, 4H), 3.33-3.28 (m, 2H), 2.93 (t, J = 6.3 Hz, 2H), 2.04 (m, 2H), 1.93-1.85 (m, 2H), 1.73 (m, 2H), 1.39-1.28 (m) , 3H);
MS m / z (ESI): 522.2 [M + H] ⁺ .

（Ｒ）－Ｎ－（５－シアノ－４－（３－メトキシピロリジン－１－イル）ピリジン－２－イル）－７－ホルミル－６－（（２－カルボニル－１,３－オキサゼパン－３－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例２９を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．５２ （ｓ, １Ｈ）, １０．２９ （ｓ, １Ｈ）, ８．２１（ｓ, １Ｈ）, ７．７１（ｓ, １Ｈ）, ７．５３ （ｄ, Ｊ ＝ ８．０ Ｈｚ, １Ｈ）, ４．９５ （ｓ, ２Ｈ）, ４．１７－４．０４ （ｍ, ５Ｈ）, ３．９０－３．７８ （ｍ, ４Ｈ）, ３．３７ （ｓ, ３Ｈ）, ３．３４－３．２７ （ｍ, ２Ｈ）, ２．９３ （ｔ, Ｊ ＝ ６．３ Ｈｚ, ２Ｈ）, ２．２５ （ｍ, １Ｈ）, ２．０９－２．００ （ｍ, ３Ｈ）, １．８８ （ｍ, ２Ｈ）, １．７７－１．６８ （ｍ, ２Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５３４．２ ［Ｍ＋Ｈ］^＋． Example 31
(R) -N- (5-cyano-4- (3-methoxypyrrolidine-1-yl) pyridine-2-yl) -7-formyl-6-((2-carbonyl-1,3-oxazepan-3-yl) Il) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

(R) -N- (5-cyano-4- (3-methoxypyrrolidine-1-yl) pyridin-2-yl) -7-formyl-6-((2-carbonyl-1,3-oxazepan-3-yl) Il) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide may be produced by referring to Example 29.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.52 (s, 1H), 10.29 (s, 1H), 8.21 (s, 1H), 7.71 (s, 1H), 7.53 (D, J = 8.0 Hz, 1H), 4.95 (s, 2H), 4.17-4.04 (m, 5H), 3.90-3.78 (m, 4H), 3. 37 (s, 3H), 3.34-3.27 (m, 2H), 2.93 (t, J = 6.3 Hz, 2H), 2.25 (m, 1H), 2.09-2 .00 (m, 3H), 1.88 (m, 2H), 1.77-1.68 (m, 2H);
MS m / z (ESI): 534.2 [M + H] ⁺ .

（Ｓ）－Ｎ－（５－シアノ－４－（３－メトキシピロリジン－１－イル）ピリジン－２－イル）－７－ホルミル－６－（（２－カルボニル－１,３－オキサゼパン－３－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例２９を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．５２ （ｓ, １Ｈ）, １０．２９ （ｓ, １Ｈ）, ８．２１（ｓ, １Ｈ）, ７．７１（ｓ, １Ｈ）, ７．５３ （ｄ, Ｊ ＝ ８．０ Ｈｚ, １Ｈ）, ４．９５ （ｓ, ２Ｈ）, ４．１７－４．０４ （ｍ, ５Ｈ）, ３．９０－３．７８ （ｍ, ４Ｈ）, ３．３７ （ｓ, ３Ｈ）, ３．３４－３．２７ （ｍ, ２Ｈ）, ２．９３ （ｔ, Ｊ ＝ ６．３ Ｈｚ, ２Ｈ）, ２．２５ （ｍ, １Ｈ）, ２．０９－２．００ （ｍ, ３Ｈ）, １．８８ （ｍ, ２Ｈ）, １．７７－１．６８ （ｍ, ２Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５３４．２ ［Ｍ＋Ｈ］^＋． Example 32
(S) -N- (5-cyano-4- (3-methoxypyrrolidine-1-yl) pyridine-2-yl) -7-formyl-6-((2-carbonyl-1,3-oxazepan-3-yl) Il) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

(S) -N- (5-cyano-4- (3-methoxypyrrolidine-1-yl) pyridin-2-yl) -7-formyl-6-((2-carbonyl-1,3-oxazepan-3-yl) Il) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide may be produced by referring to Example 29.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.52 (s, 1H), 10.29 (s, 1H), 8.21 (s, 1H), 7.71 (s, 1H), 7.53 (D, J = 8.0 Hz, 1H), 4.95 (s, 2H), 4.17-4.04 (m, 5H), 3.90-3.78 (m, 4H), 3. 37 (s, 3H), 3.34-3.27 (m, 2H), 2.93 (t, J = 6.3 Hz, 2H), 2.25 (m, 1H), 2.09-2 .00 (m, 3H), 1.88 (m, 2H), 1.77-1.68 (m, 2H);
MS m / z (ESI): 534.2 [M + H] ⁺ .

（Ｓ）－Ｎ－（５－シアノ－４－（（テトラヒドロフラン－３－イル）アミノ）ピリジン－２－イル）－７－ホルミル－６－（（２－カルボニル－１,３－オキサゼパン－３－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例２９を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３）： δ １３．６６ （ｓ, １Ｈ）, １０．２６ （ｓ, １Ｈ）, ８．２０ （ｓ, １Ｈ）, ７．７２ （ｓ, １Ｈ）, ７．６４ （ｓ, １Ｈ）, ５．１３ （ｓ, １Ｈ）, ４．９５ （ｓ, ２Ｈ）, ４．３５－４．２７ （ｍ, １Ｈ）, ４．１９－４．１３ （ｍ, ２Ｈ）, ４．１２－４．０６ （ｍ, ２Ｈ）, ４．０７－３．９８ （ｍ, ２Ｈ）, ３．８９ （ｍ, １Ｈ）, ３．８１（ｍ, １Ｈ）, ３．３５－３．２８ （ｍ, ２Ｈ）, ２．９４ （ｔ, Ｊ ＝ ６．３ Ｈｚ, ２Ｈ）, ２．４４ （ｍ, １Ｈ）, ２．０５ （ｍ, ２Ｈ）, ２．００－１．９４ （ｍ, １Ｈ）, １．８９ （ｍ, ２Ｈ）, １．７７－１．６９ （ｍ, ２Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５２０．２ ［Ｍ＋Ｈ］^＋． Example 33
(S) -N- (5-cyano-4-((tetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6-((2-carbonyl-1,3-oxazepan-3-3) Il) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

(S) -N- (5-cyano-4-((tetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6-((2-carbonyl-1,3-oxazepan-3-3) Il) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide may be produced by referring to Example 29.
^{1 1} H NMR (400 MHz, CDCl ₃ ): δ 13.66 (s, 1H), 10.26 (s, 1H), 8.20 (s, 1H), 7.72 (s, 1H), 7. 64 (s, 1H), 5.13 (s, 1H), 4.95 (s, 2H), 4.35-4.27 (m, 1H), 4.19-4.13 (m, 2H) , 4.12-4.06 (m, 2H), 4.07-3.98 (m, 2H), 3.89 (m, 1H), 3.81 (m, 1H), 3.35-3 .28 (m, 2H), 2.94 (t, J = 6.3 Hz, 2H), 2.44 (m, 1H), 2.05 (m, 2H), 2.00-1.94 ( m, 1H), 1.89 (m, 2H), 1.77-1.69 (m, 2H);
MS m / z (ESI): 520.2 [M + H] ⁺ .

（Ｒ）－Ｎ－（５－シアノ－４－（（テトラヒドロフラン－３－イル）アミノ）ピリジン－２－イル）－７－ホルミル－６－（（２－カルボニル－１,３－オキサゼパン－３－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例２９を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３）： δ １３．６６ （ｓ, １Ｈ）, １０．２６ （ｓ, １Ｈ）, ８．２０ （ｓ, １Ｈ）, ７．７２ （ｓ, １Ｈ）, ７．６４ （ｓ, １Ｈ）, ５．１３ （ｓ, １Ｈ）, ４．９５ （ｓ, ２Ｈ）, ４．３５－４．２７ （ｍ, １Ｈ）, ４．１９－４．１３ （ｍ, ２Ｈ）, ４．１２－４．０６ （ｍ, ２Ｈ）, ４．０７－３．９８ （ｍ, ２Ｈ）, ３．８９ （ｍ, １Ｈ）, ３．８１（ｍ, １Ｈ）, ３．３５－３．２８ （ｍ, ２Ｈ）, ２．９４ （ｔ, Ｊ ＝ ６．３ Ｈｚ, ２Ｈ）, ２．４４ （ｍ, １Ｈ）, ２．０５ （ｍ, ２Ｈ）, ２．００－１．９４ （ｍ, １Ｈ）, １．８９ （ｍ, ２Ｈ）, １．７７－１．６９ （ｍ, ２Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５２０．２ ［Ｍ＋Ｈ］^＋． Example 34
(R) -N- (5-cyano-4-((Tetrahydrofuran-3-yl) amino) Pyridine-2-yl) -7-formyl-6-((2-carbonyl-1,3-oxazepan-3-3) Il) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

(R) -N- (5-cyano-4-((Tetrahydrofuran-3-yl) amino) Pyridine-2-yl) -7-formyl-6-((2-carbonyl-1,3-oxazepan-3-3) Il) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide may be produced by referring to Example 29.
^{1 1} H NMR (400 MHz, CDCl ₃ ): δ 13.66 (s, 1H), 10.26 (s, 1H), 8.20 (s, 1H), 7.72 (s, 1H), 7. 64 (s, 1H), 5.13 (s, 1H), 4.95 (s, 2H), 4.35-4.27 (m, 1H), 4.19-4.13 (m, 2H) , 4.12-4.06 (m, 2H), 4.07-3.98 (m, 2H), 3.89 (m, 1H), 3.81 (m, 1H), 3.35-3 .28 (m, 2H), 2.94 (t, J = 6.3 Hz, 2H), 2.44 (m, 1H), 2.05 (m, 2H), 2.00-1.94 ( m, 1H), 1.89 (m, 2H), 1.77-1.69 (m, 2H);
MS m / z (ESI): 520.2 [M + H] ⁺ .

（Ｒ）－Ｎ－（５－シアノ－４－（（１－メトキシプロパン－２－イル）オキソ）ピリジン－２－イル）－７－ホルミル－６－（（２－カルボニル－１,３－オキサゼパン－３－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例２９を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．８６ （ｓ, １Ｈ）, １０．２７ （ｓ, １Ｈ）, ８．３６ （ｓ, １Ｈ）, ８．０６ （ｓ, １Ｈ）, ７．７３ （ｓ, １Ｈ）, ４．９５ （ｓ, ２Ｈ）, ４．９２－４．８６ （ｍ, １Ｈ）, ４．１８－４．１３ （ｍ, ２Ｈ）, ４．１１－４．０５ （ｍ, ２Ｈ）, ３．６７ （ｍ, １Ｈ）, ３．５８ （ｍ, １Ｈ）, ３．４３ （ｓ, ３Ｈ）, ３．３５－３．２９ （ｍ, ２Ｈ）, ２．９４ （ｔ, Ｊ ＝ ６．３ Ｈｚ, ２Ｈ）, ２．０９－２．０２ （ｍ, ２Ｈ）, １．９３－１．８６ （ｍ, ２Ｈ）, １．７４ （ｍ, ２Ｈ）, １．４２ （ｄ, Ｊ ＝ ６．３ Ｈｚ, ３Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５２３．２ ［Ｍ＋Ｈ］^＋． Example 35
(R) -N- (5-cyano-4-((1-methoxypropan-2-yl) oxo) pyridine-2-yl) -7-formyl-6-((2-carbonyl-1,3-oxazepan) -3-yl) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

(R) -N- (5-cyano-4-((1-methoxypropan-2-yl) oxo) pyridine-2-yl) -7-formyl-6-((2-carbonyl-1,3-oxazepan) For the method for producing -3-yl) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide, see Example 29.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.86 (s, 1H), 10.27 (s, 1H), 8.36 (s, 1H), 8.06 (s, 1H), 7.73 (S, 1H), 4.95 (s, 2H), 4.92-4.86 (m, 1H), 4.18-4.13 (m, 2H), 4.11-4.05 (m) , 2H), 3.67 (m, 1H), 3.58 (m, 1H), 3.43 (s, 3H), 3.35-3.29 (m, 2H), 2.94 (t, J = 6.3 Hz, 2H), 2.09-2.02 (m, 2H), 1.93-1.86 (m, 2H), 1.74 (m, 2H), 1.42 (d) , J = 6.3 Hz, 3H);
MS m / z (ESI): 523.2 [M + H] ⁺ .

（Ｓ）－Ｎ－（５－シアノ－４－（（テトラヒドロフラン－２－イル）チオ）ピリジン－２－イル）－７－ホルミル－６－（（２－カルボニル－１,３－オキサゼパン－３－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例２９を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．９５ （ｓ, １Ｈ）, １０．２５ （ｓ, １Ｈ）, ８．３８ （ｓ, １Ｈ）, ８．３２ （ｓ, １Ｈ）, ７．７３ （ｓ, １Ｈ）, ４．９５ （ｓ, ２Ｈ）, ４．３８ （ｍ, １Ｈ）, ４．１９－４．０６ （ｍ, ５Ｈ）, ４．０４－３．９３ （ｍ, ２Ｈ）, ３．８１（ｍ, １Ｈ）, ３．３５－３．２８ （ｍ, ２Ｈ）, ２．９５ （ｔ, Ｊ ＝ ６．１Ｈｚ, ２Ｈ）, ２．６０ （ｍ, １Ｈ）, ２．０９－２．０３ （ｍ, ３Ｈ）, １．９２－１．８８ （ｍ, ２Ｈ）, １．７４ （ｍ, ２Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５３７．２ ［Ｍ＋Ｈ］^＋． Example 36
(S) -N- (5-cyano-4-((tetrahydrofuran-2-yl) thio) pyridin-2-yl) -7-formyl-6-((2-carbonyl-1,3-oxazepan-3-3) Il) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

(S) -N- (5-cyano-4-((tetrahydrofuran-2-yl) thio) pyridin-2-yl) -7-formyl-6-((2-carbonyl-1,3-oxazepan-3-3) Il) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide may be produced by referring to Example 29.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.95 (s, 1H), 10.25 (s, 1H), 8.38 (s, 1H), 8.32 (s, 1H), 7.73 (S, 1H), 4.95 (s, 2H), 4.38 (m, 1H), 4.19-4.06 (m, 5H), 4.04-3.93 (m, 2H), 3.81 (m, 1H), 3.35-3.28 (m, 2H), 2.95 (t, J = 6.1Hz, 2H), 2.60 (m, 1H), 2.09- 2.03 (m, 3H), 1.92-1.88 (m, 2H), 1.74 (m, 2H);
MS m / z (ESI): 537.2 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（（トランス）－４－メトキシテトラヒドロフラン－３－イル）アミノ）ピリジン－２－イル）－７－ホルミル－６－（（２－カルボニル－１,３－オキサゼパン－３－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例２９を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．６６ （ｓ, １Ｈ）, １０．２３ （ｓ, １Ｈ）, ８．２１（ｓ, １Ｈ）, ７．７８ （ｓ, １Ｈ）, ７．７１（ｓ, １Ｈ）, ５．０２－４．９２ （ｍ, ３Ｈ）, ４．１７－４．０７ （ｍ, ７Ｈ）, ３．９２－３．８９ （ｍ, １Ｈ）, ３．８６－３．７９ （ｍ, ２Ｈ）, ３．５４ （ｓ, ３Ｈ）, ３．３４－３．２８ （ｍ, ２Ｈ）, ２．９４ （ｔ, Ｊ ＝ ６．３ Ｈｚ, ２Ｈ）, ２．０５－２．０２ （ｍ, ２Ｈ）, １．９３－１．８５ （ｍ, ２Ｈ）, １．７６－１．７０ （ｍ, ２Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５５０．２ ［Ｍ＋Ｈ］^＋． Example 37
N- (5-cyano-4-(((trans) -4-methoxytetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6-((2-carbonyl-1,3-oxazepan) -3-yl) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

N- (5-cyano-4-(((trans) -4-methoxytetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6-((2-carbonyl-1,3-oxazepan) For the method for producing -3-yl) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide, see Example 29.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.66 (s, 1H), 10.23 (s, 1H), 8.21 (s, 1H), 7.78 (s, 1H), 7.71 (S, 1H), 5.02-4.92 (m, 3H), 4.17-4.07 (m, 7H), 3.92-3.89 (m, 1H), 3.86-3 .79 (m, 2H), 3.54 (s, 3H), 3.34-3.28 (m, 2H), 2.94 (t, J = 6.3 Hz, 2H), 2.05- 2.02 (m, 2H), 1.93-1.85 (m, 2H), 1.76-1.70 (m, 2H);
MS m / z (ESI): 550.2 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（Ｒ）－３－メトキシピロリジン－１－イル）ピリジン－２－イル）－７－ホルミル－６－（（（Ｓ）－４－メチル－２－カルボニルオキサゾリジン－３－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例２９を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．４９ （ｓ, １Ｈ）, １０．２４ （ｓ, １Ｈ）, ８．２１（ｓ, １Ｈ）, ７．７６ （ｓ, １Ｈ）, ７．４８ （ｓ, １Ｈ）, ５．０５ （ｄ, Ｊ ＝ １６．２ Ｈｚ, １Ｈ）, ４．７９ （ｄ, Ｊ ＝ １６．２ Ｈｚ, １Ｈ）, ４．４２ （ｔ, Ｊ ＝ ８．３ Ｈｚ, １Ｈ）, ４．０９ （ｍ, ３Ｈ）, ３．９１（ｍ, １Ｈ）, ３．８８－３．７７ （ｍ, ５Ｈ）, ３．３７ （ｓ, ３Ｈ）, ２．９３ （ｔ, Ｊ ＝ ６．３ Ｈｚ, ２Ｈ）, ２．２３ （ｍ, １Ｈ）, ２．０７－２．００ （ｍ, ３Ｈ）, １．２９ （ｄ, Ｊ ＝ ６．０ Ｈｚ, ３Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５２０．２ ［Ｍ＋Ｈ］^＋． Example 38
N- (5-cyano-4-((R) -3-methoxypyrrolidine-1-yl) pyridin-2-yl) -7-formyl-6-(((S) -4-methyl-2-carbonyloxazolidine) -3-yl) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

N- (5-cyano-4-((R) -3-methoxypyrrolidine-1-yl) pyridin-2-yl) -7-formyl-6-(((S) -4-methyl-2-carbonyloxazolidine) For the method for producing -3-yl) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide, see Example 29.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.49 (s, 1H), 10.24 (s, 1H), 8.21 (s, 1H), 7.76 (s, 1H), 7.48 (S, 1H), 5.05 (d, J = 16.2 Hz, 1H), 4.79 (d, J = 16.2 Hz, 1H), 4.42 (t, J = 8.3 Hz) , 1H), 4.09 (m, 3H), 3.91 (m, 1H), 3.88-3.77 (m, 5H), 3.37 (s, 3H), 2.93 (t, J = 6.3 Hz, 2H), 2.23 (m, 1H), 2.07-2.00 (m, 3H), 1.29 (d, J = 6.0 Hz, 3H);
MS m / z (ESI): 520.2 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（Ｓ）－３－メトキシピロリジン－１－イル）ピリジン－２－イル）－７－ホルミル－６－（（（Ｓ）－４－メチル－２－カルボニルオキサゾリジン－３－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例２９を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．４８ （ｓ, １Ｈ）, １０．２５ （ｓ, １Ｈ）, ８．２１（ｓ, １Ｈ）, ７．７７ （ｓ, １Ｈ）, ７．５０ （ｓ, １Ｈ）, ５．０６ （ｄ, Ｊ ＝ １６．２ Ｈｚ, １Ｈ）, ４．７９ （ｄ, Ｊ ＝ １６．２ Ｈｚ, １Ｈ）, ４．４１（ｔ, Ｊ ＝ ８．２ Ｈｚ, １Ｈ）, ４．１１－４．０４ （ｍ, ３Ｈ）, ３．８８ （ｍ, ６Ｈ）, ３．３７ （ｓ, ３Ｈ）, ２．９３ （ｔ, Ｊ ＝ ６．３ Ｈｚ, ２Ｈ）, ２．２４ （ｍ, １Ｈ）, ２．０９－２．００ （ｍ, ３Ｈ）, １．２９ （ｄ, Ｊ ＝ ６．０ Ｈｚ, ３Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５２０．２ ［Ｍ＋Ｈ］^＋． Example 39
N- (5-cyano-4-((S) -3-methoxypyrrolidine-1-yl) pyridin-2-yl) -7-formyl-6-(((S) -4-methyl-2-carbonyloxazolidine) -3-yl) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

N- (5-cyano-4-((S) -3-methoxypyrrolidine-1-yl) pyridin-2-yl) -7-formyl-6-(((S) -4-methyl-2-carbonyloxazolidine) For the method for producing -3-yl) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide, see Example 29.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.48 (s, 1H), 10.25 (s, 1H), 8.21 (s, 1H), 7.77 (s, 1H), 7.50 (S, 1H), 5.06 (d, J = 16.2 Hz, 1H), 4.79 (d, J = 16.2 Hz, 1H), 4.41 (t, J = 8.2 Hz) , 1H), 4.11-4.04 (m, 3H), 3.88 (m, 6H), 3.37 (s, 3H), 2.93 (t, J = 6.3 Hz, 2H) , 2.24 (m, 1H), 2.09-2.00 (m, 3H), 1.29 (d, J = 6.0 Hz, 3H);
MS m / z (ESI): 520.2 [M + H] ⁺ .

（Ｓ）－Ｎ－（５－シアノ－４－（３－メトキシピロリジン－１－イル）ピリジン－２－イル）－７－ホルミル－６－（（２－カルボニルオキサゾリジン－３－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例２９を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．５５ （ｓ, １Ｈ）, １０．２１（ｓ, １Ｈ）, ８．１８ （ｓ, １Ｈ）, ７．７４ （ｓ, １Ｈ）, ７．４６ （ｓ, １Ｈ）, ４．８７ （ｓ, ２Ｈ）, ４．３５－４．３１（ｍ, ２Ｈ）, ４．０９－４．０６ （ｍ, ３Ｈ）, ３．７３－３．５４ （ｍ, ４Ｈ）, ３．５９ （ｔ, Ｊ ＝ ７．９ Ｈｚ, ２Ｈ）, ３．３７ （ｓ, ３Ｈ）, ２．９４ （ｔ, Ｊ ＝ ６．０ Ｈｚ, ２Ｈ）, ２．３１－２．１２ （ｍ, １Ｈ）, ２．１２－１．８６ （ｍ, ３Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５０６．２ ［Ｍ＋Ｈ］^＋． Example 40
(S) -N- (5-cyano-4- (3-methoxypyrrolidine-1-yl) pyridin-2-yl) -7-formyl-6-((2-carbonyloxazolidine-3-yl) methyl)- 3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

(S) -N- (5-cyano-4- (3-methoxypyrrolidine-1-yl) pyridin-2-yl) -7-formyl-6-((2-carbonyloxazolidine-3-yl) methyl)- For the method for producing 3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide, see Example 29.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.55 (s, 1H), 10.21 (s, 1H), 8.18 (s, 1H), 7.74 (s, 1H), 7.46 (S, 1H), 4.87 (s, 2H), 4.35-4.31 (m, 2H), 4.09-4.06 (m, 3H), 3.73-3.54 (m) , 4H), 3.59 (t, J = 7.9 Hz, 2H), 3.37 (s, 3H), 2.94 (t, J = 6.0 Hz, 2H), 2.31-2 .12 (m, 1H), 2.12-1.86 (m, 3H);
MS m / z (ESI): 506.2 [M + H] ⁺ .

（Ｒ）－Ｎ－（５－シアノ－４－（３－メトキシピロリジン－１－イル）ピリジン－２－イル）－７－ホルミル－６－（（２－カルボニルオキサゾリジン－３－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例２９を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．５５ （ｓ, １Ｈ）, １０．２１（ｓ, １Ｈ）, ８．１８ （ｓ, １Ｈ）, ７．７４ （ｓ, １Ｈ）, ７．４６ （ｓ, １Ｈ）, ４．８７ （ｓ, ２Ｈ）, ４．３５－４．３１（ｍ, ２Ｈ）, ４．０９－４．０６ （ｍ, ３Ｈ）, ３．７３－３．５４ （ｍ, ４Ｈ）, ３．５９ （ｔ, Ｊ ＝ ７．９ Ｈｚ, ２Ｈ）, ３．３７ （ｓ, ３Ｈ）, ２．９４ （ｔ, Ｊ ＝ ６．０ Ｈｚ, ２Ｈ）, ２．３１－２．１２ （ｍ, １Ｈ）, ２．１２－１．８６ （ｍ, ３Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５０６．２ ［Ｍ＋Ｈ］^＋． Example 41
(R) -N- (5-cyano-4- (3-methoxypyrrolidine-1-yl) pyridin-2-yl) -7-formyl-6-((2-carbonyloxazolidine-3-yl) methyl)- 3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

(R) -N- (5-cyano-4- (3-methoxypyrrolidine-1-yl) pyridin-2-yl) -7-formyl-6-((2-carbonyloxazolidine-3-yl) methyl)- For the method for producing 3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide, see Example 29.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.55 (s, 1H), 10.21 (s, 1H), 8.18 (s, 1H), 7.74 (s, 1H), 7.46 (S, 1H), 4.87 (s, 2H), 4.35-4.31 (m, 2H), 4.09-4.06 (m, 3H), 3.73-3.54 (m) , 4H), 3.59 (t, J = 7.9 Hz, 2H), 3.37 (s, 3H), 2.94 (t, J = 6.0 Hz, 2H), 2.31-2 .12 (m, 1H), 2.12-1.86 (m, 3H);
MS m / z (ESI): 506.2 [M + H] ⁺ .

（Ｒ）－Ｎ－（５－シアノ－４－（（１－メトキシプロパン－２－イル）オキソ）ピリジン－２－イル）－７－ホルミル－６－（（５－カルボニル－６－オキサ－４－アザスピロ［２．４］ヘプタン－４－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例２９を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．７６ （ｓ, １Ｈ）, １０．２１（ｓ, １Ｈ）, ８．３４ （ｓ, １Ｈ）, ８．０１（ｓ, １Ｈ）, ７．７０ （ｓ, １Ｈ）, ４．８９－４．８５ （ｍ, １Ｈ）, ４．７０ （ｓ, ２Ｈ）, ４．３９ （ｓ, ２Ｈ）, ４．１１－４．０８ （ｍ, ２Ｈ）, ３．６９－３．６４ （ｍ, １Ｈ）, ３．６０－３．５６ （ｍ, １Ｈ）, ３．４３ （ｓ, ３Ｈ）, ２．９７ （ｔ, Ｊ ＝ ６．２ Ｈｚ, ２Ｈ）, ２．０７－２．０５ （ｍ, ２Ｈ）, １．４２－１．４１（ｍ, ３Ｈ）, ０．９７－０．９４ （ｍ, ２Ｈ）, ０．６６－０．６２ （ｍ, ２Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５２１．２ ［Ｍ＋Ｈ］^＋． Example 42
(R) -N- (5-cyano-4-((1-methoxypropan-2-yl) oxo) pyridine-2-yl) -7-formyl-6-((5-carbonyl-6-oxa-4) -Azaspiro [2.4] heptane-4-yl) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

(R) -N- (5-cyano-4-((1-methoxypropan-2-yl) oxo) pyridine-2-yl) -7-formyl-6-((5-carbonyl-6-oxa-4) -Refer to Example 29 for the method for producing azaspiro [2.4] heptane-4-yl) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.76 (s, 1H), 10.21 (s, 1H), 8.34 (s, 1H), 8.01 (s, 1H), 7.70 (S, 1H), 4.89-4.85 (m, 1H), 4.70 (s, 2H), 4.39 (s, 2H), 4.11-4.08 (m, 2H), 3.69-3.64 (m, 1H), 3.60-3.56 (m, 1H), 3.43 (s, 3H), 2.97 (t, J = 6.2 Hz, 2H) , 2.07-2.05 (m, 2H), 1.42-1.41 (m, 3H), 0.97-0.94 (m, 2H), 0.66-0.62 (m, 2H);
MS m / z (ESI): 521.2 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（２－メトキシエチル）アミノ）ピリジン－２－イル）－７－ホルミル－６－（（５－カルボニル－６－オキサ－４－アザスピロ［２．４］ヘプタン－４－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例２９を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．４６ （ｓ, １Ｈ）, １０．１４ （ｓ, １Ｈ）, ８．１０ （ｓ, １Ｈ）, ７．６２ （ｓ, １Ｈ）, ７．５０ （ｓ, １Ｈ）, ４．６３ （ｓ, ２Ｈ）,４．３２ （ｓ, ２Ｈ）, ４．０１（ｍ, ２Ｈ）, ３．５７－３．３４ （ｍ, ８Ｈ）, ２．８８ （ｍ, ２Ｈ）, １．９８ （ｍ, ２Ｈ）, ０．８８ （ｍ, ２Ｈ）, ０．５６ （ｍ, ２Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５０６．２ ［Ｍ＋Ｈ］^＋． Example 43
N- (5-cyano-4-((2-Methoxyethyl) amino) pyridin-2-yl) -7-formyl-6-((5-carbonyl-6-oxa-4-azaspiro [2.4] heptane) -4-yl) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

N- (5-cyano-4-((2-Methoxyethyl) amino) pyridin-2-yl) -7-formyl-6-((5-carbonyl-6-oxa-4-azaspiro [2.4] heptane) For the method for producing -4-yl) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide, see Example 29.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.46 (s, 1H), 10.14 (s, 1H), 8.10 (s, 1H), 7.62 (s, 1H), 7.50 (S, 1H), 4.63 (s, 2H), 4.32 (s, 2H), 4.01 (m, 2H), 3.57-3.34 (m, 8H), 2.88 ( m, 2H), 1.98 (m, 2H), 0.88 (m, 2H), 0.56 (m, 2H);
MS m / z (ESI): 506.2 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（（Ｒ）－テトラヒドロフラン－３－イル）チオ）ピリジン－２－イル）－７－ホルミル－６－（（（Ｓ）－４－メチル－２－カルボニルオキサゾリジン－３－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例２９を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．９０ （ｓ, １Ｈ）, １０．２３ （ｓ, １Ｈ）, ８．３７ （ｓ, １Ｈ）, ８．２８ （ｓ, １Ｈ）, ７．７９ （ｓ, １Ｈ）, ５．０５ （ｄ, Ｊ ＝ １６．４ Ｈｚ, １Ｈ）, ４．８０ （ｄ, Ｊ ＝ １６．４ Ｈｚ, １Ｈ）, ４．３５ （ ｍ, ２Ｈ）, ４．０９ （ｍ, ３Ｈ）, ３．８５ （ｍ, ５Ｈ）, ２．９５ （ｍ, ２Ｈ）, ２．５９ （ｍ, １Ｈ）, ２．０６ （ｍ, ３Ｈ）, １．２８ （ｍ, ３Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５２３．１［Ｍ＋Ｈ］^＋． Example 44
N- (5-cyano-4-(((R) -tetrahydrofuran-3-yl) thio) pyridine-2-yl) -7-formyl-6-(((S) -4-methyl-2-carbonyloxazolidine) -3-yl) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

N- (5-cyano-4-(((R) -tetrahydrofuran-3-yl) thio) pyridine-2-yl) -7-formyl-6-(((S) -4-methyl-2-carbonyloxazolidine) For the method for producing -3-yl) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide, see Example 29.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.90 (s, 1H), 10.23 (s, 1H), 8.37 (s, 1H), 8.28 (s, 1H), 7.79 (S, 1H), 5.05 (d, J = 16.4 Hz, 1H), 4.80 (d, J = 16.4 Hz, 1H), 4.35 (m, 2H), 4.09 (M, 3H), 3.85 (m, 5H), 2.95 (m, 2H), 2.59 (m, 1H), 2.06 (m, 3H), 1.28 (m, 3H) ;
MS m / z (ESI): 523.1 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（（Ｓ）－テトラヒドロフラン－３－イル）チオ）ピリジン－２－イル）－７－ホルミル－６－（（（Ｓ）－４－メチル－２－カルボニルオキサゾリジン－３－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例２９を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．９０ （ｓ, １Ｈ）, １０．２３ （ｓ, １Ｈ）, ８．３７ （ｓ, １Ｈ）, ８．２８ （ｓ, １Ｈ）, ７．７９ （ｓ, １Ｈ）, ５．０５ （ｄ, Ｊ ＝ １６．４ Ｈｚ, １Ｈ）, ４．８０ （ｄ, Ｊ ＝ １６．４ Ｈｚ, １Ｈ）, ４．３５ （ ｍ, ２Ｈ）, ４．０９ （ｍ, ３Ｈ）, ３．８５ （ｍ, ５Ｈ）, ２．９５ （ｍ, ２Ｈ）, ２．５９ （ｍ, １Ｈ）, ２．０６ （ｍ, ３Ｈ）, １．２８ （ｍ, ３Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５２３．１［Ｍ＋Ｈ］^＋． Example 45
N- (5-cyano-4-(((S) -tetrahydrofuran-3-yl) thio) pyridine-2-yl) -7-formyl-6-(((S) -4-methyl-2-carbonyloxazolidine) -3-yl) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

N- (5-cyano-4-(((S) -tetrahydrofuran-3-yl) thio) pyridine-2-yl) -7-formyl-6-(((S) -4-methyl-2-carbonyloxazolidine) For the method for producing -3-yl) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide, see Example 29.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.90 (s, 1H), 10.23 (s, 1H), 8.37 (s, 1H), 8.28 (s, 1H), 7.79 (S, 1H), 5.05 (d, J = 16.4 Hz, 1H), 4.80 (d, J = 16.4 Hz, 1H), 4.35 (m, 2H), 4.09 (M, 3H), 3.85 (m, 5H), 2.95 (m, 2H), 2.59 (m, 1H), 2.06 (m, 3H), 1.28 (m, 3H) ;
MS m / z (ESI): 523.1 [M + H] ⁺ .

Ｎ－（５－シアノ－４－トランス－（（（３,４）－４－メトキシテトラヒドロフラン－３－イル）アミノ）ピリジン－２－イル）－７－ホルミル－６－（（（Ｓ）－４－メチル－２－カルボニルオキサゾリジン－３－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例２９を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３）： δ １３．６４ （ｓ, １Ｈ）, １０．２４ （ｓ, １Ｈ）, ８．２１（ｓ, １Ｈ）, ７．７８ （ｄ, Ｊ ＝ ４．１Ｈｚ, ２Ｈ）, ５．０１（ｍ, １Ｈ）, ４．７９ （ｍ, １Ｈ）, ４．５１（ｍ, １Ｈ）, ４．４３ （ｍ, １Ｈ）, ４．１４ （ｍ, ２Ｈ）, ４．０９ （ｍ, ２Ｈ）, ４．０２ （ｍ, １Ｈ）, ３．９６ （ｍ, １Ｈ）, ３．９１（ｍ, ２Ｈ）, ３．８４ （ｍ, ２Ｈ）, ３．５４ （ｓ, ３Ｈ）, ２．９５ （ｔ, Ｊ ＝ ６．２ Ｈｚ, ２Ｈ）, ２．０３ （ｍ, ２Ｈ）, １．３１（ｄ, Ｊ ＝ ６．１Ｈｚ, ３Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５３６．２ ［Ｍ＋Ｈ］^＋． Example 46
N- (5-Cyano-4-trans-(((3,4) -4-methoxytetratetra-3-yl) amino) Pyridine-2-yl) -7-formyl-6-(((S) -4) -Methyl-2-carbonyloxazolidine-3-yl) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

N- (5-Cyano-4-trans-(((3,4) -4-methoxytetratetra-3-yl) amino) Pyridine-2-yl) -7-formyl-6-(((S) -4) -Methyl-2-carbonyloxazolidine-3-yl) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide can be produced by referring to Example 29.
^{1 1} H NMR (400 MHz, CDCl ₃ ): δ 13.64 (s, 1H), 10.24 (s, 1H), 8.21 (s, 1H), 7.78 (d, J = 4.1 Hz) , 2H), 5.01 (m, 1H), 4.79 (m, 1H), 4.51 (m, 1H), 4.43 (m, 1H), 4.14 (m, 2H), 4 .09 (m, 2H), 4.02 (m, 1H), 3.96 (m, 1H), 3.91 (m, 2H), 3.84 (m, 2H), 3.54 (s, 3H), 2.95 (t, J = 6.2 Hz, 2H), 2.03 (m, 2H), 1.31 (d, J = 6.1 Hz, 3H);
MS m / z (ESI): 536.2 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（（３,４）－トランス－４－メトキシテトラヒドロフラン－３－イル）オキソ）ピリジン－２－イル）－７－ホルミル－６－（（（Ｓ）－４－メチル－２－カルボニルオキサゾリジン－３－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例２９を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．９０ （ｓ, １Ｈ）, １０．２５ （ｓ, １Ｈ）, ８．３８ （ｓ, １Ｈ）, ８．０３ （ｓ, １Ｈ）, ７．７９ （ｓ, １Ｈ）, ５．０５ （ｍ, ２Ｈ）, ４．８１（ｍ, １Ｈ）, ４．４３（ ｍ, １Ｈ）, ４．２７ （ｍ, １Ｈ）, ４．１２ （ｍ, ４Ｈ）, ３．９３ （ｍ, ４Ｈ）, ３．４８ （ｓ, ３Ｈ）, ２．９５ （ｍ, ２Ｈ）, ２．０７ （ｍ, ２Ｈ）, １．３０ （ｍ, ３Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５３７．２ ［Ｍ＋Ｈ］^＋． Example 47
N- (5-cyano-4-(((3,4) -trans-4-methoxytetrahydrofuran-3-yl) oxo) pyridin-2-yl) -7-formyl-6-(((S) -4) -Methyl-2-carbonyloxazolidine-3-yl) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

N- (5-cyano-4-(((3,4) -trans-4-methoxytetratetra-3-yl) oxo) pyridin-2-yl) -7-formyl-6-(((S) -4) -Methyl-2-carbonyloxazolidine-3-yl) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide can be produced by referring to Example 29.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.90 (s, 1H), 10.25 (s, 1H), 8.38 (s, 1H), 8.03 (s, 1H), 7.79 (S, 1H), 5.05 (m, 2H), 4.81 (m, 1H), 4.43 (m, 1H), 4.27 (m, 1H), 4.12 (m, 4H) , 3.93 (m, 4H), 3.48 (s, 3H), 2.95 (m, 2H), 2.07 (m, 2H), 1.30 (m, 3H);
MS m / z (ESI): 537.2 [M + H] ⁺ .

（Ｒ）－Ｎ－（５－シアノ－４－（（１－メトキシプロパン－２－イル）オキソ）ピリジン－２－イル）－７－ホルミル－６－（（２－チオオキサゾリジン－３－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例２９を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．７７ （ｓ, １Ｈ）, １０．２３ （ｓ, １Ｈ）, ８．３４ （ｓ, １Ｈ）, ８．０１（ｓ, １Ｈ）, ７．９８ （ｓ, １Ｈ）, ５．３５ （ｓ, ２Ｈ）, ４．８９－４．８５ （ｍ, １Ｈ）, ４．６１－４．４７ （ｍ, ２Ｈ）, ４．１５－４．０５ （ｍ, ２Ｈ）, ３．８０ （ｔ, Ｊ ＝ ８．８ Ｈｚ, ２Ｈ）, ３．６９－３．６５ （ｍ, １Ｈ）, ３．６０－３．５６ （ｍ, １Ｈ）, ３．４３ （ｓ, ３Ｈ）, ２．９７ （ｔ, Ｊ ＝ ６．２ Ｈｚ, ２Ｈ）, ２．０９－２．０５ （ｍ, ２Ｈ）, １．４２ （ｄ, Ｊ ＝ ６．３ Ｈｚ, ３Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５１１．２ ［Ｍ＋Ｈ］^＋． Example 48
(R) -N- (5-cyano-4-((1-methoxypropan-2-yl) oxo) pyridine-2-yl) -7-formyl-6-((2-thiooxazolidine-3-yl)) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

(R) -N- (5-cyano-4-((1-methoxypropan-2-yl) oxo) pyridine-2-yl) -7-formyl-6-((2-thiooxazolidine-3-yl)) Example 29 may be referred to for a method for producing methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.77 (s, 1H), 10.23 (s, 1H), 8.34 (s, 1H), 8.01 (s, 1H), 7.98 (S, 1H), 5.35 (s, 2H), 4.89-4.85 (m, 1H), 4.61-4.47 (m, 2H), 4.15-4.05 (m) , 2H), 3.80 (t, J = 8.8 Hz, 2H), 3.69-3.65 (m, 1H), 3.60-3.56 (m, 1H), 3.43 ( s, 3H), 2.97 (t, J = 6.2 Hz, 2H), 2.09-2.05 (m, 2H), 1.42 (d, J = 6.3 Hz, 3H);
MS m / z (ESI): 511.2 [M + H] ⁺ .

（Ｒ）－Ｎ－（５－シアノ－４－（３－メトキシピロリジン－１－イル）ピリジン－２－イル）－７－ホルミル－６－（（２－カルボニル－１,３－オキサジナン－３－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例２９を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．５２ （ｓ, １Ｈ）, １０．２３ （ｓ, １Ｈ）, ８．２１（ｓ, １Ｈ）, ７．７７ （ｓ, １Ｈ）, ７．４８ （ｓ, １Ｈ）, ５．０２ （ｓ, ２Ｈ）, ４．３４－４．２８ （ｍ, ２Ｈ）, ４．１２－４．０５ （ｍ, ３Ｈ）, ３．８６－３．７７ （ｍ, ４Ｈ）, ３．３９－３．３２ （ｍ, ５Ｈ）, ２．９３ （ｔ, Ｊ ＝ ６．１Ｈｚ, ２Ｈ）, ２．０９－１．９８ （ｍ, ６Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５２０．２ ［Ｍ＋Ｈ］^＋． Example 49
(R) -N- (5-cyano-4- (3-methoxypyrrolidine-1-yl) pyridine-2-yl) -7-formyl-6-((2-carbonyl-1,3-oxadinane-3-3) Il) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

(R) -N- (5-cyano-4- (3-methoxypyrrolidine-1-yl) pyridin-2-yl) -7-formyl-6-((2-carbonyl-1,3-oxadinane-3-3) Il) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide may be produced by referring to Example 29.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.52 (s, 1H), 10.23 (s, 1H), 8.21 (s, 1H), 7.77 (s, 1H), 7.48 (S, 1H), 5.02 (s, 2H), 4.34-4.28 (m, 2H), 4.12-4.05 (m, 3H), 3.86-3.77 (m) , 4H), 3.39-3.32 (m, 5H), 2.93 (t, J = 6.1Hz, 2H), 2.09-1.98 (m, 6H);
MS m / z (ESI): 520.2 [M + H] ⁺ .

（Ｓ）－Ｎ－（５－シアノ－４－（３－メトキシピロリジン－１－イル）ピリジン－２－イル）－７－ホルミル－６－（（２－カルボニル－１,３－オキサジナン－３－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例２９を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．５２ （ｓ, １Ｈ）, １０．２３ （ｓ, １Ｈ）, ８．２０ （ｓ, １Ｈ）, ７．７６ （ｓ, １Ｈ）, ７．４７ （ｓ, １Ｈ）, ５．０２ （ｓ, ２Ｈ）, ４．３４－４．２８ （ｍ, ２Ｈ）, ４．１０－４．０５ （ｍ, ３Ｈ）, ３．８３－３．７６ （ｍ, ４Ｈ）, ３．３８－３．３４ （ｍ, ５Ｈ）, ２．９３ （ｔ, Ｊ ＝ ６．３ Ｈｚ, ２Ｈ）, ２．１１－１．９６ （ｍ, ６Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５２０．２ ［Ｍ＋Ｈ］^＋． Example 50
(S) -N- (5-cyano-4- (3-methoxypyrrolidine-1-yl) pyridine-2-yl) -7-formyl-6-((2-carbonyl-1,3-oxadinane-3-3) Il) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

(S) -N- (5-cyano-4- (3-methoxypyrrolidine-1-yl) pyridin-2-yl) -7-formyl-6-((2-carbonyl-1,3-oxadinane-3-3) Il) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide may be produced by referring to Example 29.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.52 (s, 1H), 10.23 (s, 1H), 8.20 (s, 1H), 7.76 (s, 1H), 7.47 (S, 1H), 5.02 (s, 2H), 4.34-4.28 (m, 2H), 4.10-4.05 (m, 3H), 3.83-3.76 (m) , 4H), 3.38-3.34 (m, 5H), 2.93 (t, J = 6.3 Hz, 2H), 2.11-1.96 (m, 6H);
MS m / z (ESI): 520.2 [M + H] ⁺ .

（Ｓ）－Ｎ－（５－シアノ－４－（３－メトキシピロリジン－１－イル）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．５０ （ｓ, １Ｈ）, １０．２３ （ｓ, １Ｈ）, ８．２０ （ｓ, １Ｈ）, ７．６６ （ｓ, １Ｈ）, ７．４８ （ｓ, １Ｈ）, ５．１１（ｓ, ２Ｈ）, ４．２５ （ｓ, ２Ｈ）, ４．０８ （ｍ, ３Ｈ）, ３．９１－３．８７ （ｍ, ２Ｈ）, ３．８０ （ｍ, ４Ｈ）, ３．４３－３．３９ （ｍ, ２Ｈ）, ３．３７ （ｓ, ３Ｈ）, ２．９３ （ｍ, ２Ｈ）, ２．２６－２．１９ （ｍ, １Ｈ）, ２．０８－２．０１（ｍ, ３Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５２０．２ ［Ｍ＋Ｈ］^＋． Example 51
(S) -N- (5-cyano-4- (3-methoxypyrrolidin-1-yl) pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4- Dihydro-1,8-diazonaphthalene-1 (2H) -formamide

(S) -N- (5-cyano-4- (3-methoxypyrrolidin-1-yl) pyridin-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4- Example 1 may be referred to for a method for producing dihydro-1,8-diazonaphthalene-1 (2H) -formamide.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.50 (s, 1H), 10.23 (s, 1H), 8.20 (s, 1H), 7.66 (s, 1H), 7.48 (S, 1H), 5.11 (s, 2H), 4.25 (s, 2H), 4.08 (m, 3H), 3.91-3.87 (m, 2H), 3.80 ( m, 4H), 3.43-3.39 (m, 2H), 3.37 (s, 3H), 2.93 (m, 2H), 2.26-2.19 (m, 1H), 2 .08-2.01 (m, 3H);
MS m / z (ESI): 520.2 [M + H] ⁺ .

（Ｒ）－Ｎ－（５－シアノ－４－（３－メトキシピロリジン－１－イル）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．５０ （ｓ, １Ｈ）, １０．２３ （ｓ, １Ｈ）, ８．２０ （ｓ, １Ｈ）, ７．６６ （ｓ, １Ｈ）, ７．４８ （ｓ, １Ｈ）, ５．１１（ｓ, ２Ｈ）, ４．２５ （ｓ, ２Ｈ）, ４．０８ （ｍ, ３Ｈ）, ３．９１－３．８７ （ｍ, ２Ｈ）, ３．８０ （ｍ, ４Ｈ）, ３．４３－３．３９ （ｍ, ２Ｈ）, ３．３７ （ｓ, ３Ｈ）, ２．９３ （ｍ, ２Ｈ）, ２．２６－２．１９ （ｍ, １Ｈ）, ２．０８－２．０１（ｍ, ３Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５２０．２ ［Ｍ＋Ｈ］^＋． Example 52
(R) -N- (5-cyano-4- (3-methoxypyrrolidin-1-yl) pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4- Dihydro-1,8-diazonaphthalene-1 (2H) -formamide

(R) -N- (5-cyano-4- (3-methoxypyrrolidin-1-yl) pyridin-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4- Example 1 may be referred to for a method for producing dihydro-1,8-diazonaphthalene-1 (2H) -formamide.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.50 (s, 1H), 10.23 (s, 1H), 8.20 (s, 1H), 7.66 (s, 1H), 7.48 (S, 1H), 5.11 (s, 2H), 4.25 (s, 2H), 4.08 (m, 3H), 3.91-3.87 (m, 2H), 3.80 ( m, 4H), 3.43-3.39 (m, 2H), 3.37 (s, 3H), 2.93 (m, 2H), 2.26-2.19 (m, 1H), 2 .08-2.01 (m, 3H);
MS m / z (ESI): 520.2 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（３－メトキシアゼチジニル－１－イル）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＤＭＳＯ－ｄ_６）： δ １３．４６ （ｓ, １Ｈ）, １０．３４ （ｓ, １Ｈ）, ８．１５ （ｓ, １Ｈ）, ７．７１（ｓ, １Ｈ）, ７．３１（ｓ, １Ｈ）, ５．１３ （ｓ, ２Ｈ）, ４．６０ （ｍ, ２Ｈ）, ４．３８ （ｍ, ２Ｈ）, ４．２９ （ｍ, ２Ｈ）, ４．２４ （ｓ, １Ｈ）, ３．８９ （ｍ, ２Ｈ）,４．０４ （ｍ, ２Ｈ）, ３．４２ （ｍ, ２Ｈ）, ３．３６ （ｓ, ３Ｈ）, ２．９２ （ｍ, ２Ｈ）, ２．０５ （ｍ, ２Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５０６．２ ［Ｍ＋Ｈ］^＋． Example 53
N- (5-Cyano-4- (3-methoxyazetidineyl-1-yl) pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4-dihydro- 1,8-Diazonaphthalene-1 (2H) -formamide

N- (5-Cyano-4- (3-methoxyazetidineyl-1-yl) pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4-dihydro- Example 1 may be referred to for the method for producing 1,8-diazonaphthalene-1 (2H) -formamide.
^{1 1} H NMR (400 MHz, DMSO-d ₆ ): δ 13.46 (s, 1H), 10.34 (s, 1H), 8.15 (s, 1H), 7.71 (s, 1H), 7.31 (s, 1H), 5.13 (s, 2H), 4.60 (m, 2H), 4.38 (m, 2H), 4.29 (m, 2H), 4.24 (s) , 1H), 3.89 (m, 2H), 4.04 (m, 2H), 3.42 (m, 2H), 3.36 (s, 3H), 2.92 (m, 2H), 2 .05 (m, 2H);
MS m / z (ESI): 506.2 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（メトキシアミノ）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＤＭＳＯ－ｄ_６）： δ １３．０６ （ｓ, １Ｈ）, １０．６６ （ｓ, １Ｈ）, １０．１３ （ｓ, １Ｈ）, ８．４０ （ｓ, １Ｈ）, ７．７６ （ｓ, １Ｈ）, ７．６４ （ｓ, １Ｈ）, ４．９３ （ｓ, ２Ｈ）, ４．１６ （ｓ, ２Ｈ）, ３．９６ （ｍ, ２Ｈ）, ３．８９ （ｍ, ２Ｈ）, ３．６８ （ｍ, ３Ｈ）, ３．３６ （ｍ, ２Ｈ）, ２．９１（ｍ, ２Ｈ）, １．９７ （ｍ, ２Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ４６６．１［Ｍ＋Ｈ］^＋． Example 54
N- (5-Cyano-4- (methoxyamino) pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

N- (5-Cyano-4- (methoxyamino) pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 Example 1 may be referred to for the method for producing (2H) -formamide.
^{1 1} H NMR (400 MHz, DMSO-d ₆ ): δ 13.06 (s, 1H), 10.66 (s, 1H), 10.13 (s, 1H), 8.40 (s, 1H), 7.76 (s, 1H), 7.64 (s, 1H), 4.93 (s, 2H), 4.16 (s, 2H), 3.96 (m, 2H), 3.89 (m) , 2H), 3.68 (m, 3H), 3.36 (m, 2H), 2.91 (m, 2H), 1.97 (m, 2H);
MS m / z (ESI): 466.1 [M + H] ⁺ .

（Ｓ）－Ｎ－（５－シアノ－４－（（テトラヒドロフラン－３－イル）チオ）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．９０ （ｓ, １Ｈ）, １０．２３ （ｓ, １Ｈ）, ８．３７ （ｓ, １Ｈ）, ８．２８ （ｓ, １Ｈ）, ７．６９ （ｓ, １Ｈ）, ５．１１（ｓ, ２Ｈ）, ４．４０－４．３２ （ｍ, １Ｈ）, ４．２６ （ｓ, ２Ｈ）, ４．１３－４．０６ （ｍ, ３Ｈ）, ４．０２－３．９６ （ｍ, ２Ｈ）, ３．９４－３．８６ （ｍ, ２Ｈ）, ３．８４－３．７６ （ｍ, １Ｈ）, ３．４５－３．４０ （ｍ, ２Ｈ）, ２．９５ （ｔ, Ｊ ＝ ６．２ Ｈｚ, ２Ｈ）, ２．６４－２．５５ （ｍ, １Ｈ）, ２．１０－２．０２ （ｍ, ３Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５２３．１［Ｍ＋Ｈ］^＋． Example 55
(S) -N- (5-cyano-4-((tetrahydrofuran-3-yl) thio) pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4- Dihydro-1,8-diazonaphthalene-1 (2H) -formamide

(S) -N- (5-cyano-4-((tetrahydrofuran-3-yl) thio) pyridin-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4- Example 1 may be referred to for the method for producing dihydro-1,8-diazonaphthalene-1 (2H) -formamide.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.90 (s, 1H), 10.23 (s, 1H), 8.37 (s, 1H), 8.28 (s, 1H), 7.69 (S, 1H), 5.11 (s, 2H), 4.40-4.32 (m, 1H), 4.26 (s, 2H), 4.13-4.06 (m, 3H), 4.02-3.96 (m, 2H), 3.94-3.86 (m, 2H), 3.84-3.76 (m, 1H), 3.45-3.40 (m, 2H) ), 2.95 (t, J = 6.2 Hz, 2H), 2.64-2.55 (m, 1H), 2.10-2.02 (m, 3H);
MS m / z (ESI): 523.1 [M + H] ⁺ .

（Ｒ）－Ｎ－（５－シアノ－４－（（テトラヒドロフラン－３－イル）チオ）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．９０ （ｓ, １Ｈ）, １０．２３ （ｓ, １Ｈ）, ８．３７ （ｓ, １Ｈ）, ８．２８ （ｓ, １Ｈ）, ７．６９ （ｓ, １Ｈ）, ５．１１（ｓ, ２Ｈ）, ４．４０－４．３２ （ｍ, １Ｈ）, ４．２６ （ｓ, ２Ｈ）, ４．１３－４．０６ （ｍ, ３Ｈ）, ４．０２－３．９６ （ｍ, ２Ｈ）, ３．９４－３．８６ （ｍ, ２Ｈ）, ３．８４－３．７６ （ｍ, １Ｈ）, ３．４５－３．４０ （ｍ, ２Ｈ）, ２．９５ （ｔ, Ｊ ＝ ６．２ Ｈｚ, ２Ｈ）, ２．６４－２．５５ （ｍ, １Ｈ）, ２．１０－２．０２ （ｍ, ３Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５２３．１［Ｍ＋Ｈ］^＋． Example 56
(R) -N- (5-cyano-4-((tetrahydrofuran-3-yl) thio) pyridin-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4- Dihydro-1,8-diazonaphthalene-1 (2H) -formamide

(R) -N- (5-cyano-4-((tetrahydrofuran-3-yl) thio) pyridin-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4- Example 1 may be referred to for the method for producing dihydro-1,8-diazonaphthalene-1 (2H) -formamide.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.90 (s, 1H), 10.23 (s, 1H), 8.37 (s, 1H), 8.28 (s, 1H), 7.69 (S, 1H), 5.11 (s, 2H), 4.40-4.32 (m, 1H), 4.26 (s, 2H), 4.13-4.06 (m, 3H), 4.02-3.96 (m, 2H), 3.94-3.86 (m, 2H), 3.84-3.76 (m, 1H), 3.45-3.40 (m, 2H) ), 2.95 (t, J = 6.2 Hz, 2H), 2.64-2.55 (m, 1H), 2.10-2.02 (m, 3H);
MS m / z (ESI): 523.1 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（（２－メトキシピリジン－３－イル）メチル）アミノ）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３）： δ １３．５６ （ｓ, １Ｈ）, １０．２２ （ｓ, １Ｈ）, ８．１８ （ｓ, １Ｈ）, ８．１３ （ｄｄ, Ｊ ＝ ５．２, １．６ Ｈｚ, １Ｈ）, ７．６８ （ｓ, １Ｈ）, ７．６６ （ｓ, １Ｈ）, ７．６１（ｄｄ, Ｊ ＝ ６．０, １．６ Ｈｚ, １Ｈ）, ６．８９ （ｍ, １Ｈ）, ５．５８ （ｍ, １Ｈ）, ５．１１（ｓ, ２Ｈ）, ４．４９ （ｄ, Ｊ ＝ ６．０ Ｈｚ, ２Ｈ）, ４．２５ （ｓ, ２Ｈ）, ４．１０ （ｍ, ２Ｈ）, ４．０４ （ｓ, ３Ｈ）, ３．８９ （ｍ, ２Ｈ）, ３．４１（ｔ, Ｊ ＝ ５．２ Ｈｚ, ２Ｈ）, ２．９３ （ｔ, Ｊ ＝ ６．０ Ｈｚ, ２Ｈ）, ２．０５ （ｍ, ２Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５５７．２ ［Ｍ＋Ｈ］^＋． Example 57
N- (5-cyano-4-(((2-methoxypyridine-3-yl) methyl) amino) pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3, 4-Dihydro-1,8-diazonaphthalene-1 (2H) -formamide

N- (5-cyano-4-(((2-Methoxypyridine-3-yl) methyl) amino) Pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3, Example 1 may be referred to for a method for producing 4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide.
^{1 1} H NMR (400 MHz, CDCl ₃ ): δ 13.56 (s, 1H), 10.22 (s, 1H), 8.18 (s, 1H), 8.13 (dd, J = 5.2) , 1.6 Hz, 1H), 7.68 (s, 1H), 7.66 (s, 1H), 7.61 (dd, J = 6.0, 1.6 Hz, 1H), 6.89 (M, 1H), 5.58 (m, 1H), 5.11 (s, 2H), 4.49 (d, J = 6.0 Hz, 2H), 4.25 (s, 2H), 4 .10 (m, 2H), 4.04 (s, 3H), 3.89 (m, 2H), 3.41 (t, J = 5.2 Hz, 2H), 2.93 (t, J = 6.0 Hz, 2H), 2.05 (m, 2H);
MS m / z (ESI): 557.2 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（４－メトキシピリジン－３－イル）アミノ）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．６４ （ｓ, １Ｈ）, １０．２３ （ｓ, １Ｈ）, ８．６５ （ｓ, １Ｈ）, ８．４２ （ｄ, Ｊ ＝ ５．６ Ｈｚ, １Ｈ）, ８．３３ （ｓ, １Ｈ）, ７．９２ （ｓ, １Ｈ）, ７．６５ （ｓ, １Ｈ）, ６．９５ （ｄ, Ｊ ＝ ５．６ Ｈｚ, １Ｈ）, ６．６１（ｓ, １Ｈ）, ５．１０ （ｓ, ２Ｈ）, ４．２５ （ｓ, ２Ｈ）,４．０２－４．０１（ｍ, ２Ｈ）, ３．９６ （ｓ, ３Ｈ）, ３．９１－３．８４ （ｍ, ２Ｈ）, ３．４４－３．３４ （ｍ, ２Ｈ）, ２．９１（ｔ, Ｊ ＝ ６．２ Ｈｚ, ２Ｈ）, ２．０２－１．９９ （ｍ, ２Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５４３．２ ［Ｍ＋Ｈ］^＋． Example 58
N- (5-cyano-4-((4-Methoxypyridine-3-yl) amino) Pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4-dihydro -1,8-Diazonaphthalene-1 (2H) -formamide

N- (5-cyano-4-((4-Methoxypyridine-3-yl) amino) Pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4-dihydro Example 1 may be referred to for the method for producing -1,8-diazonaphthalene-1 (2H) -formamide.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.64 (s, 1H), 10.23 (s, 1H), 8.65 (s, 1H), 8.42 (d, J = 5.6 Hz) , 1H), 8.33 (s, 1H), 7.92 (s, 1H), 7.65 (s, 1H), 6.95 (d, J = 5.6 Hz, 1H), 6.61 (S, 1H), 5.10 (s, 2H), 4.25 (s, 2H), 4.02-4.01 (m, 2H), 3.96 (s, 3H), 3.91- 3.84 (m, 2H), 3.44-3.34 (m, 2H), 2.91 (t, J = 6.2 Hz, 2H), 2.02-1.99 (m, 2H) ;
MS m / z (ESI): 543.2 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（（１Ｓ、２Ｓ）－２－メトキシシクロペンチル）アミノ）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造は実施例１を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．５６ （ｓ, １Ｈ）, １０．２３ （ｓ, １Ｈ）, ８．１７ （ｓ, １Ｈ）, ７．７３ （ｓ, １Ｈ）, ７．６６ （ｓ, １Ｈ）, ５．１１（ｓ, ２Ｈ）, ４．８７ （ｍ, １Ｈ）, ４．２６ （ｓ, ２Ｈ）, ４．０９ （ｍ, ２Ｈ）, ３．９３－３．８５ （ｍ, ３Ｈ）, ３．６９ （ｍ, １Ｈ）, ３．４２－３．３９ （ｍ, ４Ｈ）, ２．９３ （ｍ, ２Ｈ）, ２．３３ （ｍ, １Ｈ）, ２．０７－２．０１（ｍ, ２Ｈ）, １．９５ － １．５０ （ｍ, ６Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５３４．２ ［Ｍ＋Ｈ］^＋． Example 59
N- (5-cyano-4-(((1S, 2S) -2-methoxycyclopentyl) amino) pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4 -Dihydro-1,8-diazonaphthalene-1 (2H) -formamide

N- (5-cyano-4-(((1S, 2S) -2-methoxycyclopentyl) amino) pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4 For the production of -dihydro-1,8-diazonaphthalene-1 (2H) -formamide, see Example 1.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.56 (s, 1H), 10.23 (s, 1H), 8.17 (s, 1H), 7.73 (s, 1H), 7.66 (S, 1H), 5.11 (s, 2H), 4.87 (m, 1H), 4.26 (s, 2H), 4.09 (m, 2H), 3.93-3.85 ( m, 3H), 3.69 (m, 1H), 3.42-3.39 (m, 4H), 2.93 (m, 2H), 2.33 (m, 1H), 2.07-2 0.01 (m, 2H), 1.95-1.50 (m, 6H);
MS m / z (ESI): 534.2 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（（１Ｒ、２Ｒ）－２－メトキシシクロペンチル）アミノ）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造は実施例１を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．５６ （ｓ, １Ｈ）, １０．２３ （ｓ, １Ｈ）, ８．１７ （ｓ, １Ｈ）, ７．７３ （ｓ, １Ｈ）, ７．６６ （ｓ, １Ｈ）, ５．１１（ｓ, ２Ｈ）, ４．８７ （ｍ, １Ｈ）, ４．２６ （ｓ, ２Ｈ）, ４．０９ （ｍ, ２Ｈ）, ３．９３－３．８５ （ｍ, ３Ｈ）, ３．６９ （ｍ, １Ｈ）, ３．４２－３．３９ （ｍ, ４Ｈ）, ２．９３ （ｍ, ２Ｈ）, ２．３３ （ｍ, １Ｈ）, ２．０７－２．０１（ｍ, ２Ｈ）, １．９５ － １．５０ （ｍ, ６Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５３４．２ ［Ｍ＋Ｈ］^＋． Example 60
N- (5-cyano-4-(((1R, 2R) -2-methoxycyclopentyl) amino) pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4 -Dihydro-1,8-diazonaphthalene-1 (2H) -formamide

N- (5-cyano-4-(((1R, 2R) -2-methoxycyclopentyl) amino) pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4 For the production of -dihydro-1,8-diazonaphthalene-1 (2H) -formamide, see Example 1.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.56 (s, 1H), 10.23 (s, 1H), 8.17 (s, 1H), 7.73 (s, 1H), 7.66 (S, 1H), 5.11 (s, 2H), 4.87 (m, 1H), 4.26 (s, 2H), 4.09 (m, 2H), 3.93-3.85 ( m, 3H), 3.69 (m, 1H), 3.42-3.39 (m, 4H), 2.93 (m, 2H), 2.33 (m, 1H), 2.07-2 0.01 (m, 2H), 1.95-1.50 (m, 6H);
MS m / z (ESI): 534.2 [M + H] ⁺ .

Ｎ－（５－シアノ－４－トランス－（（１、２）－２－メトキシシクロブトキシ）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造は実施例１を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３）： δ １３．８３ （ｓ, １Ｈ）, １０．２３ （ｓ, １Ｈ）, ８．３６ （ｓ, １Ｈ）, ８．００ （ｓ, １Ｈ）, ７．６８ （ｓ, １Ｈ）, ５．１１（ｓ, ２Ｈ）, ４．６８ （ｍ, １Ｈ）, ４．２６ （ｓ, ２Ｈ）, ４．１５－４．０３ （ｍ, ３Ｈ）, ３．９５－３．８４ （ｍ, ２Ｈ）, ３．４５－３．３５ （ｍ, ５Ｈ）, ２．９５ （ｔ, Ｊ ＝ ６．２ Ｈｚ, ２Ｈ）, ２．４３ （ｍ, １Ｈ）, ２．２９－２．２０ （ｍ, １Ｈ）, ２．０５ （ｍ, ２Ｈ）, １．７２－１．６３ （ｍ, ２Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５２１．２ ［Ｍ＋Ｈ］^＋． Example 61
N- (5-Cyano-4-trans-((1,2) -2-methoxycyclobutoxy) pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4 -Dihydro-1,8-diazonaphthalene-1 (2H) -formamide

N- (5-Cyano-4-trans-((1,2) -2-methoxycyclobutoxy) pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4 For the production of -dihydro-1,8-diazonaphthalene-1 (2H) -formamide, see Example 1.
^{1 1} H NMR (400 MHz, CDCl ₃ ): δ 13.83 (s, 1H), 10.23 (s, 1H), 8.36 (s, 1H), 8.00 (s, 1H), 7. 68 (s, 1H), 5.11 (s, 2H), 4.68 (m, 1H), 4.26 (s, 2H), 4.15-4.03 (m, 3H), 3.95 -3.84 (m, 2H), 3.45-3.35 (m, 5H), 2.95 (t, J = 6.2 Hz, 2H), 2.43 (m, 1H), 2. 29-2.20 (m, 1H), 2.05 (m, 2H), 1.72-1.63 (m, 2H);
MS m / z (ESI): 521.2 [M + H] ⁺ .

Ｎ－（５－シアノ－４－シス－（（１、２）－２－メトキシシクロブトキシ）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ_３）： δ １３．８３ （ｓ， １Ｈ）， １０．２５ （ｓ， １Ｈ）， ８．３７ （ｓ， １Ｈ）， ７．８９ （ｓ， １Ｈ）， ７．６９ （ｓ， １Ｈ）， ５．１２ （ｓ， ２Ｈ）， ４．９５ （ｍ， １Ｈ）， ４．３０－４．２０ （ｍ， ３Ｈ）， ４．０９ （ｍ， ２Ｈ）， ３．９２－３．８４ （ｍ， ２Ｈ）， ３．４５－３．３８ （ｍ， ５Ｈ）， ２．９５ （ｔ， Ｊ ＝ ６．２ Ｈｚ， ２Ｈ）， ２．４０ （ｍ， ２Ｈ）， ２．１５ （ｍ， ２Ｈ）， ２．０５ （ｍ， ２Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５２１．２ ［Ｍ＋Ｈ］^＋． Example 62
N- (5-Cyano-4-cis- ((1,2) -2-methoxycyclobutoxy) pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4 -Dihydro-1,8-diazonaphthalene-1 (2H) -formamide

N- (5-Cyano-4-cis- ((1,2) -2-methoxycyclobutoxy) pyridine-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3,4 For the method for producing -dihydro-1,8-diazonaphthalene-1 (2H) -formamide, see Example 1.
^{1 1} H NMR (400 MHz, CDCl ₃ ): δ 13.83 (s, 1H), 10.25 (s, 1H), 8.37 (s, 1H), 7.89 (s, 1H), 7. 69 (s, 1H), 5.12 (s, 2H), 4.95 (m, 1H), 4.30-4.20 (m, 3H), 4.09 (m, 2H), 3.92 -3.84 (m, 2H), 3.45-3.38 (m, 5H), 2.95 (t, J = 6.2 Hz, 2H), 2.40 (m, 2H), 2. 15 (m, 2H), 2.05 (m, 2H);
MS m / z (ESI): 521.2 [M + H] ⁺ .

（Ｓ）－Ｎ－（５－シアノ－４－（３－メトキシピロリジン－１－イル）ピリジン－２－イル）－７－ホルミル－６－（（４－メチル－２－カルボニルピペラジン－１－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．５１（ｓ, １Ｈ）, １０．２３ （ｓ, １Ｈ）, ８．２０ （ｓ, １Ｈ）, ７．６７ （ｓ, １Ｈ）, ７．４８ （ｓ, １Ｈ）, ５．０９ （ｓ, ２Ｈ）, ４．０７ （ ｍ, ３Ｈ）, ３．８１（ｍ, ４Ｈ）, ３．３７ （ｍ, ５Ｈ）, ３．２４ （ｍ, ２Ｈ）,２．９３ （ｍ, ２Ｈ）, ２．７１（ｍ, ２Ｈ）, ２．３９ （ｍ, ３Ｈ）, ２．２１（ｍ, １Ｈ） , ２．０２ （ｍ, ３Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５３３．２ ［Ｍ＋Ｈ］^＋． Example 63
(S) -N- (5-cyano-4- (3-methoxypyrrolidine-1-yl) pyridin-2-yl) -7-formyl-6-((4-methyl-2-carbonylpiperazin-1-yl) ) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

(S) -N- (5-cyano-4- (3-methoxypyrrolidine-1-yl) pyridin-2-yl) -7-formyl-6-((4-methyl-2-carbonylpiperazin-1-yl) ) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide may be produced by referring to Example 1.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.51 (s, 1H), 10.23 (s, 1H), 8.20 (s, 1H), 7.67 (s, 1H), 7.48 (S, 1H), 5.09 (s, 2H), 4.07 (m, 3H), 3.81 (m, 4H), 3.37 (m, 5H), 3.24 (m, 2H) , 2.93 (m, 2H), 2.71 (m, 2H), 2.39 (m, 3H), 2.21 (m, 1H), 2.02 (m, 3H);
MS m / z (ESI): 533.2 [M + H] ⁺ .

（Ｒ）－Ｎ－（５－シアノ－４－（３－メトキシピロリジン－１－イル）ピリジン－２－イル）－７－ホルミル－６－（（４－メチル－２－カルボニルピペラジン－１－イル）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．５１（ｓ, １Ｈ）, １０．２３ （ｓ, １Ｈ）, ８．２０ （ｓ, １Ｈ）, ７．６７ （ｓ, １Ｈ）, ７．４８ （ｓ, １Ｈ）, ５．０９ （ｓ, ２Ｈ）, ４．０７ （ ｍ, ３Ｈ）, ３．８１（ｍ, ４Ｈ）, ３．３７ （ｍ, ５Ｈ）, ３．２４ （ｍ, ２Ｈ）,２．９３ （ｍ, ２Ｈ）, ２．７１（ｍ, ２Ｈ）, ２．３９ （ｍ, ３Ｈ）, ２．２１（ｍ, １Ｈ） , ２．０２ （ｍ, ３Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５３３．２ ［Ｍ＋Ｈ］^＋． Example 64
(R) -N- (5-cyano-4- (3-methoxypyrrolidine-1-yl) pyridin-2-yl) -7-formyl-6-((4-methyl-2-carbonylpiperazin-1-yl) ) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

(R) -N- (5-cyano-4- (3-methoxypyrrolidine-1-yl) pyridin-2-yl) -7-formyl-6-((4-methyl-2-carbonylpiperazin-1-yl) ) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide may be produced by referring to Example 1.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.51 (s, 1H), 10.23 (s, 1H), 8.20 (s, 1H), 7.67 (s, 1H), 7.48 (S, 1H), 5.09 (s, 2H), 4.07 (m, 3H), 3.81 (m, 4H), 3.37 (m, 5H), 3.24 (m, 2H) , 2.93 (m, 2H), 2.71 (m, 2H), 2.39 (m, 3H), 2.21 (m, 1H), 2.02 (m, 3H);
MS m / z (ESI): 533.2 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（２－メトキシエチル）アミノ）ピリジン－２－イル）－６－（（４－シクロプロピル－２－カルボニルピペラジン－１－イル）メチル）－７－ホルミル－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ_３）： δ １３．６０ （ｓ， １Ｈ）， １０．２２ （ｓ， １Ｈ）， ８．１８ （ｓ， １Ｈ）， ７．６３ （ｓ， １Ｈ）， ７．５６ （ｓ， １Ｈ）， ５．３０ （ｍ， １Ｈ）， ５．０６ （ｓ， ２Ｈ）， ４．０７ （ｍ， ２Ｈ）， ３．６４ （ｍ， ２Ｈ）， ３．４９ （ｍ， ２Ｈ）， ３．４１（ｓ， ３Ｈ）， ３．３９ （ｓ， ２Ｈ）， ３．３０ （ｔ， Ｊ ＝ ５．６ Ｈｚ， ２Ｈ）， ２．９２ （ｔ， Ｊ ＝ ６．４ Ｈｚ， ２Ｈ）， ２．８６ （ｔ， Ｊ ＝ ５．６ Ｈｚ， ２Ｈ）， ２．０３ （ｍ， ２Ｈ）， １．７０ （ｍ， １Ｈ）， ０．５１（ｍ， ２Ｈ）， ０．４４ （ｍ， ２Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５３３．２ ［Ｍ＋Ｈ］^＋． Example 65
N- (5-Cyano-4-((2-methoxyethyl) amino) Pyridine-2-yl) -6-((4-Cyclopropyl-2-carbonylpiperazin-1-yl) methyl) -7-formyl- 3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

N- (5-Cyano-4-((2-methoxyethyl) amino) Pyridine-2-yl) -6-((4-Cyclopropyl-2-carbonylpiperazin-1-yl) methyl) -7-formyl- Example 1 may be referred to for the method for producing 3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide.
^{1 1} H NMR (400 MHz, CDCl ₃ ): δ 13.60 (s, 1H), 10.22 (s, 1H), 8.18 (s, 1H), 7.63 (s, 1H), 7. 56 (s, 1H), 5.30 (m, 1H), 5.06 (s, 2H), 4.07 (m, 2H), 3.64 (m, 2H), 3.49 (m, 2H) ), 3.41 (s, 3H), 3.39 (s, 2H), 3.30 (t, J = 5.6 Hz, 2H), 2.92 (t, J = 6.4 Hz, 2H) ), 2.86 (t, J = 5.6 Hz, 2H), 2.03 (m, 2H), 1.70 (m, 1H), 0.51 (m, 2H), 0.44 (m) , 2H);
MS m / z (ESI): 533.2 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（（トランス）－４－メトキシテトラヒドロフラン－３－イル）アミノ）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ_３） δ １３．６５ （ｓ， １Ｈ）， １０．２３ （ｓ， １Ｈ）， ８．２１（ｓ， １Ｈ）， ７．７７ （ｓ， １Ｈ）， ７．６７ （ｓ， １Ｈ）， ５．１１（ｓ， ２Ｈ）， ４．９９ （ｄ， Ｊ ＝ ６．２ Ｈｚ， １Ｈ）， ４．２６ （ｓ， ２Ｈ）， ４．１６－４．０６ （ｍ， ５Ｈ）， ３．９３－３．８７ （ｍ， ３Ｈ）， ３．８６－３．８０ （ｍ， ２Ｈ）， ３．５４ （ｓ， ３Ｈ）， ３．４４－３．３９ （ｍ， ２Ｈ）， ２．９４ （ｔ， Ｊ ＝ ６．２ Ｈｚ， ２Ｈ）， ２．０９－２．０１（ｍ， ２Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５３６．２ ［Ｍ＋Ｈ］^＋． Example 66
N- (5-cyano-4-(((trans) -4-methoxytetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3 , 4-Dihydro-1,8-diazonaphthalene-1 (2H) -formamide

N- (5-cyano-4-(((trans) -4-methoxytetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6-((3-carbonylmorpholino) methyl) -3 For the method for producing, 4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide, see Example 1.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.65 (s, 1H), 10.23 (s, 1H), 8.21 (s, 1H), 7.77 (s, 1H), 7.67 (S, 1H), 5.11 (s, 2H), 4.99 (d, J = 6.2 Hz, 1H), 4.26 (s, 2H), 4.16-4.06 (m, 1H) 5H), 3.93-3.87 (m, 3H), 3.86-3.80 (m, 2H), 3.54 (s, 3H), 3.44-3.39 (m, 2H) , 2.94 (t, J = 6.2 Hz, 2H), 2.09-2.01 (m, 2H);
MS m / z (ESI): 536.2 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（（３,４）－トランス－４－メトキシテトラヒドロフラン－３－イル）オキソ）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．９１（ｓ, １Ｈ）, １０．２４ （ｓ, １Ｈ）, ８．３８ （ｓ, １Ｈ）, ８．００ （ｓ, １Ｈ）, ７．６９ （ｓ, １Ｈ）, ５．１１（ｄ, Ｊ ＝ ２．０ Ｈｚ, ２Ｈ）, ５．００ （ｄ, Ｊ ＝ ４．４ Ｈｚ, １Ｈ）, ４．２７ （ ｍ, ３Ｈ）, ４．１１（ｍ, ４Ｈ）, ３．８９ （ｍ, ４Ｈ）, ３．５０ （ｓ, ３Ｈ）, ３．４３ （ｍ, ２Ｈ）, ２．９３ （ｍ, ２Ｈ）, ２．０４ （ｍ, ２Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５３７．２ ［Ｍ＋Ｈ］^＋． Example 67
N- (5-cyano-4-(((3,4) -trans-4-methoxytetrahydrofuran-3-yl) oxo) pyridin-2-yl) -7-formyl-6-((3-carbonylmorpholino)) Methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

N- (5-cyano-4-(((3,4) -trans-4-methoxytetrahydrofuran-3-yl) oxo) pyridin-2-yl) -7-formyl-6-((3-carbonylmorpholino)) Example 1 may be referred to for the method for producing methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.91 (s, 1H), 10.24 (s, 1H), 8.38 (s, 1H), 8.00 (s, 1H), 7.69 (S, 1H), 5.11 (d, J = 2.0 Hz, 2H), 5.00 (d, J = 4.4 Hz, 1H), 4.27 (m, 3H), 4.11 (M, 4H), 3.89 (m, 4H), 3.50 (s, 3H), 3.43 (m, 2H), 2.93 (m, 2H), 2.04 (m, 2H) ;
MS m / z (ESI): 537.2 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（（３,４）－トランス－４－メトキシテトラヒドロ－２Ｈ－ピラン－３－イル）オキソ）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ_３） δ １３．８３ （ｓ， １Ｈ）， １０．２５ （ｓ， １Ｈ）， ８．３７ （ｓ， １Ｈ）， ８．１０ （ｓ， １Ｈ）， ７．６９ （ｓ， １Ｈ）， ５．１１（ｓ， ２Ｈ）， ４．５４ （ｍ， １Ｈ）， ４．２５ （ｓ， ２Ｈ）， ４．１３－４．０５ （ｍ， ３Ｈ）， ３．９９－３．８５ （ｍ， ３Ｈ）， ３．６０ （ｍ， １Ｈ）， ３．５６－３．４８ （ｍ， ２Ｈ）， ３．４６ （ｓ， ３Ｈ）， ３．４４－３．３９ （ｍ， ２Ｈ）， ２．９４ （ｔ， Ｊ ＝ ６．２ Ｈｚ， ２Ｈ）， ２．２６－２．１７ （ｍ， １Ｈ）， ２．０９－２．０２ （ｍ， ２Ｈ）， １．７３ （ｍ， １Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５５１．２ ［Ｍ＋Ｈ］^＋． Example 68
N- (5-Cyano-4-(((3,4) -Trans-4-methoxytetrahydro-2H-pyran-3-yl) oxo) Pyridine-2-yl) -7-formyl-6-((3) -Carbonylmorpholino) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

N- (5-Cyano-4-(((3,4) -Trans-4-methoxytetrahydro-2H-pyran-3-yl) oxo) Pyridine-2-yl) -7-formyl-6-((3) For the method for producing -carbonylmorpholino) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide, see Example 1.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.83 (s, 1H), 10.25 (s, 1H), 8.37 (s, 1H), 8.10 (s, 1H), 7.69 (S, 1H), 5.11 (s, 2H), 4.54 (m, 1H), 4.25 (s, 2H), 4.13-4.05 (m, 3H), 3.99- 3.85 (m, 3H), 3.60 (m, 1H), 3.56-3.48 (m, 2H), 3.46 (s, 3H), 3.44-3.39 (m, 3H) 2H), 2.94 (t, J = 6.2 Hz, 2H), 2.26-2.17 (m, 1H), 2.09-2.02 (m, 2H), 1.73 (m) , 1H);
MS m / z (ESI): 551.2 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（（３,４）－トランス－３－メトキシテトラヒドロ－２Ｈ－ピラン－４－イル）オキソ）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ_３） δ １３．８７ （ｓ， １Ｈ）， １０．２６ （ｓ， １Ｈ）， ８．３８ （ｓ， １Ｈ）， ８．０８ （ｓ， １Ｈ）， ７．７０ （ｓ， １Ｈ）， ５．１２ （ｓ， ２Ｈ）， ４．６７ （ｔ， Ｊ ＝ ９．８ Ｈｚ， １Ｈ）， ４．２５ （ｓ， ２Ｈ）， ４．０８ （ｍ， ３Ｈ）， ３．９３ （ｍ， ３Ｈ）， ３．５８ （ｍ， １Ｈ）， ３．５１（ｓ， ３Ｈ）， ３．４９－３．３９ （ｍ， ４Ｈ）， ２．９５ （ｔ， Ｊ ＝ ６．２ Ｈｚ， ２Ｈ）， ２．３２－２．２４ （ｍ， １Ｈ）， ２．１０－２．０２ （ｍ， ２Ｈ）， １．９３－１．８３ （ｍ， １Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５５１．２ ［Ｍ＋Ｈ］^＋． Example 69
N- (5-Cyano-4-(((3,4) -Trans-3-methoxytetrahydro-2H-pyran-4-yl) oxo) Pyridine-2-yl) -7-formyl-6-((3) -Carbonylmorpholino) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

N- (5-Cyano-4-(((3,4) -Trans-3-methoxytetrahydro-2H-pyran-4-yl) oxo) Pyridine-2-yl) -7-formyl-6-((3) For the method for producing -carbonylmorpholino) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide, see Example 1.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.87 (s, 1H), 10.26 (s, 1H), 8.38 (s, 1H), 8.08 (s, 1H), 7.70 (S, 1H), 5.12 (s, 2H), 4.67 (t, J = 9.8 Hz, 1H), 4.25 (s, 2H), 4.08 (m, 3H), 3 .93 (m, 3H), 3.58 (m, 1H), 3.51 (s, 3H), 3.49-3.39 (m, 4H), 2.95 (t, J = 6.2) Hz, 2H), 2.32-2.24 (m, 1H), 2.10-2.02 (m, 2H), 1.93-1.83 (m, 1H);
MS m / z (ESI): 551.2 [M + H] ⁺ .

Ｎ－（５－シアノ－４－（（（３,４）－トランス－４－メトキシテトラヒドロ－２Ｈ－ピラン－３－イル）アミノ）ピリジン－２－イル）－７－ホルミル－６－（（３－カルボニルモルホリノ）メチル）－３,４－ジヒドロ－１,８－ジアゾナフタレン－１（２Ｈ）－ホルムアミドの製造方法は実施例１を参照すればよい。
^１Ｈ ＮＭＲ （４００ ＭＨｚ, ＣＤＣｌ_３） δ １３．５９ （ｓ, １Ｈ）, １０．２５ （ｓ, １Ｈ）, ８．１９ （ｓ, １Ｈ）, ７．７４ （ｓ, １Ｈ）, ７．６７ （ｓ, １Ｈ）, ５．１１（ｓ, ２Ｈ）, ４．９８ （ｓ, １Ｈ）, ４．２５ （ｓ, ２Ｈ）, ４．１６ （ｍ, １Ｈ）, ４．１１－４．０６ （ｍ, ２Ｈ）, ３．９８－３．９２ （ｍ, １Ｈ）, ３．９０－３．８６ （ｍ, ２Ｈ）, ３．７５－３．６６ （ｍ, １Ｈ）, ３．５５ （ｍ, １Ｈ）, ３．４４－３．３９ （ｍ, ５Ｈ）, ３．３３－３．２０ （ｍ, ２Ｈ）, ２．９３ （ｔ, Ｊ ＝ ６．３ Ｈｚ, ２Ｈ）, ２．２１（ｍ, １Ｈ）, ２．０６－２．０２ （ｍ, ２Ｈ）, １．６７ （ｍ, １Ｈ）；
ＭＳ ｍ／ｚ （ＥＳＩ）： ５５０．２ ［Ｍ＋Ｈ］^＋． Example 70
N- (5-Cyano-4-(((3,4) -Trans-4-methoxytetrahydro-2H-pyran-3-yl) amino) Pyridine-2-yl) -7-formyl-6-((3) -Carbonylmorpholino) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide

N- (5-Cyano-4-(((3,4) -Trans-4-methoxytetrahydro-2H-pyran-3-yl) amino) Pyridine-2-yl) -7-formyl-6-((3) For the method for producing -carbonylmorpholino) methyl) -3,4-dihydro-1,8-diazonaphthalene-1 (2H) -formamide, refer to Example 1.
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 13.59 (s, 1H), 10.25 (s, 1H), 8.19 (s, 1H), 7.74 (s, 1H), 7.67 (S, 1H), 5.11 (s, 2H), 4.98 (s, 1H), 4.25 (s, 2H), 4.16 (m, 1H), 4.11-4.06 ( m, 2H), 3.98-3.92 (m, 1H), 3.90-3.86 (m, 2H), 3.75-3.66 (m, 1H), 3.55 (m, 1H) 1H), 3.44-3.39 (m, 5H), 3.33-3.20 (m, 2H), 2.93 (t, J = 6.3 Hz, 2H), 2.21 (m) , 1H), 2.06-2.02 (m, 2H), 1.67 (m, 1H);
MS m / z (ESI): 550.2 [M + H] ⁺ .

Biological testing and evaluation

1. 1. FGFR4 Enzymology Experiment In this experiment, the inhibitory effect of a compound on FGFR4 kinase activity is tested by the fluorescence resonance energy transfer (TR-FRET) method to obtain a half-inhibition concentration _IC50 of FGFR4 kinase activity by the compound.
1) Add 1 to 5 uL of FGFR4 enzyme solution to a 384-well plate to bring the final enzyme concentration to 0.1 to 5 nM.
2) Add 1 to 5 uL of gradient diluted compound solution.
3) Add 1 to 5 uL of the substrate mixture to bring the final concentration of the substrate polypeptide to 5 to 50 nM and the final concentration of ATP to 10 to 200 uM.
4) Incubate at room temperature for 0.5-3 hours.
5) Add 10 uL of EDTA and a test solution containing a labeled antibody, and incubate at room temperature for 1 hour.
6) Measure the 665 nm fluorescence signal value of each well using a microplate reader.
7) Calculate the inhibition rate from the fluorescence signal value.
8) Based on the inhibition rates at different concentrations, curve fitting gives _IC50s of the compounds, and Table 1 shows the enzymatic activity of specific examples.

2. FGFR1 Enzymology Experiment In this experiment, the inhibitory effect of a compound on FGFR1 kinase activity is tested by the fluorescence resonance energy transfer (TR-FRET) method to obtain an IC ₅₀ with a half-inhibition concentration of FGFR1 kinase activity by the compound.
1) Add 1 to 5 uL of FGFR1 enzyme solution to a 384-well plate to bring the final enzyme concentration to 0.1 to 5 nM.
2) Add 1 to 5 uL of gradient diluted compound solution.
3) Add 1 to 5 uL of the substrate mixture to bring the final concentration of the substrate polypeptide to 5 to 50 nM and the final concentration of ATP to 10 to 200 uM.
4) Incubate at room temperature for 0.5-3 hours.
5) Add 10 uL of EDTA and a test solution containing a labeled antibody, and incubate at room temperature for 1 hour.
6) Measure the 665 nm fluorescence signal value of each well using a microplate reader.
7) Calculate the inhibition rate from the fluorescence signal value.
8) Based on the inhibition rates at different concentrations, curve fitting gives _IC50s of the compounds, and Table 1 shows the enzymatic activity of specific examples.

As can be seen from the enzyme activity data of the example compounds, the compound series of the present invention has a high inhibitory effect on FGFR4 kinase activity, whereas it has almost no inhibitory effect on FGFR1 kinase activity. Therefore, the compound series of the present invention has very high selectivity for FGFR4 kinase activity.

3. 3. Hep 3B cell proliferation inhibition experiment In this experiment, the inhibitory effect of the compound on Hep 3B cell proliferation is tested by the CellTiter-Glo method, and a half-inhibition concentration IC ₅₀ of the cell proliferation activity by the compound is obtained.
1) A 96-well cell culture plate is inoculated with 50 to 100 uL of Hep 3B cell suspension at a density of 1 to 5 × 10 ⁴ cells / mL, and the culture plate is cultured in an incubator for 16 to 24 hours (37 ° C., 5% CO ₂ ).
2) Add a solution of the compound to be measured gradient-diluted to different concentrations to the culture plate cells, and incubate the culture plate in an incubator for 72 hours (37 ° C., 5% CO ₂ ).
3) Add 50 to 100 uL of CellTiter-Glo reagent to each well and shake or let stand at room temperature for 5 to 30 minutes.
4) Measure the chemiluminescence signal value of each plate using a microplate reader.
5) Calculate the inhibition rate from the chemiluminescence signal value.
6) Based on the inhibition rates at different concentrations, curve fitting gives _IC50s of the compounds, and Table 2 shows the cell activity of specific examples.

4. HuH-7 cell proliferation inhibition experiment In this experiment, the inhibitory effect of a compound on HuH-7 cell proliferation is tested by the CellTiter-Glo method to obtain an IC ₅₀ that inhibits half of the cell proliferation activity of the compound.
1) A 96-well cell culture plate is inoculated with 50 to 100 uL of HuH-7 cell suspension at a density of 1 to 5 × 10 ⁴ cells / mL, and the culture plate is cultured in an incubator for 16 to 24 hours (37 ° C.). 5% CO ₂ ).
2) Add a solution of the compound to be measured gradient-diluted to different concentrations to the culture plate cells, and incubate the culture plate in an incubator for 72 hours (37 ° C., 5% CO ₂ ).
3) Add 50 to 100 uL of CellTiter-Glo reagent to each well and shake or let stand at room temperature for 5 to 30 minutes.
4) Measure the chemiluminescence signal value of each plate using a microplate reader.
5) Calculate the inhibition rate from the chemiluminescence signal value.
6) Based on the inhibition rates at different concentrations, curve fitting gives _IC50s of the compounds, and Table 2 shows the cell activity of specific examples.

5. SK-HEP-1 cell proliferation inhibition experiment In this experiment, the inhibitory effect of the compound on SK-HEP-1 cell proliferation is tested by the CellTiter-Glo method, and a half-inhibition concentration _IC50 of the cell proliferation activity by the compound is obtained.
1) A 96-well cell culture plate is inoculated with 50 to 100 uL of SK-HEP-1 cell suspension at a density of 1 to 5 × 10 ⁴ cells / mL, and the culture plate is cultured in an incubator for 16 to 24 hours ( 37 ° C, 5% CO ₂ ).
2) Add a solution of the compound to be measured gradient-diluted to different concentrations to the culture plate cells, and incubate the culture plate in an incubator for 72 hours (37 ° C., 5% CO ₂ ).
3) Add 50 to 100 uL of CellTiter-Glo reagent to each well and shake or let stand at room temperature for 5 to 30 minutes.
4) Measure the chemiluminescence signal value of each plate using a microplate reader.
5) Calculate the inhibition rate from the chemiluminescence signal value.
6) Based on the inhibition rates at different concentrations, curve fitting gives _IC50s of the compounds, and Table 2 shows the cell activity of specific examples.

As can be seen from the cell activity data of the example compounds, the compound series of the present invention has a high inhibitory effect on Hep3B and HuH-7 cell proliferation activity in which FGF19 and FGFR4 are highly expressed, whereas FGF19 and It has no inhibitory effect on SK-HEP-1 cell proliferation in which FGFR4 is underexpressed, and exhibits excellent cell activity and selectivity.

6. PK analysis of rats

In a preferred embodiment of the present invention, a pharmacokinetic test of rats is performed using SD rats (Shanghai Jiyi Experimental Animal Co., Ltd.).
Administration method: Single forced oral administration.
Dosage: 5 milligrams / 10 milliliters / kilogram.
Formulation Formulation: 0.5% CMC and 1% Tween 80, ultrasonic dissolution.
Sampling time: 0.5, 1, 2, 4, 6, 8 and 24 hours after administration.
Sample treatment 1) Collect 0.2 mL of venous blood, put it in a K2EDTA test tube, centrifuge at 1000 to 3000 xg for 5 to 20 minutes at room temperature to separate plasma, and store at -80 ° C.
2) 40 uL of plasma sample is added to 160 uL of acetonitrile to precipitate, and after mixing, centrifugation is performed at 500 to 2000 × g for 5 to 20 minutes.
3) The concentration of the compound to be measured is analyzed by LC / MS / MS using 100 uL of the supernatant solution after the treatment, and the LC / MS / MS analyzer is AB Siex API 4000.
n Liquid phase analysis:
l Liquid phase condition: Shimadzu LC-20AD pump
l Chromatography column: phenomenex Gemiu 5 um C18 50 × 4.6 mm
l Mobile phase: Liquid A is a 0.1% aqueous solution of formic acid, and liquid B is acetonitrile.
Flow velocity: 0.8 mL / min
Elution time: 0-3.5 minutes, eluent is as follows.

Pharmacokinetics:
The main parameters were calculated by WinNonlin 6.1, and the results of rat pharmacokinetic experiments are shown in Table 3.

As can be seen from the results of the pharmacokinetic experiments of rats in the table, the example compounds of the present invention show excellent metabolic properties, and both the exposure amount AUC and the maximum blood concentration C _max are good.

7. Steps and results of in vivo drug efficacy experiments

7.1 Objectives of experiments In vivo drug efficacy experiments are used to screen compounds with remarkable drug efficacy and low toxicity and side effects.

7.2 Main equipment and reagents for the experiment 7.2.1 Equipment:
1. Clean bench (BSC-1300II A2, manufactured by Shanghai Expo Business Co., Ltd. Medical Device Factory)
2. CO2 incubator (Thermo)
3. Centrifuge (Centrifuge 5720R, Eppendorf)
4. Automatic cell counter (Countess II, Life)
5. Pipette (10-20uL, Eppendorf)
6. Microscope (TS100, manufactured by Nikon)
6, Nogisu (500-196, made by Mitutoyo Japan)
7. Cell culture flask (T25 / T75 / T225, Corning)
7.2.2 Reagent 1, MEM medium (11095-080, gibico)
2. Fetal bovine serum (FBS) (10099-141, gibico)
3,0.25% trypsin (25200-056, gibico)
4. Penicillin / streptomycin double antibody (SV30010, GE)
5. Phosphate buffer (PBS) (10010-023, gigico)

7.3 Experimental Step 7.3.1 Cell Culture and Preparation of Cell Suspension a, Take a line of Hep 3B cells from the cell bank and thaw the cells using MEM medium (MEM + 10% FBS + 1% Glu + 1% SP). Then, the thawed cells are placed in a cell culture flask (mark the cell type, date, name of the incubator, etc. on the flask wall) and cultured in a CO2 incubator (the incubator has a temperature of 37 ° C. and a CO2 concentration of 5%). ).
b. When cells grow to 80-90% of the bottom of the culture flask, they are subcultured and the subcultured cells are placed in a CO2 incubator and cultured. The process is repeated until the number of cells meets the requirements for in vivo drug efficacy experiments.
c. Collect the cultured cells, count them with an automatic cell counter, resuspend the cells with PBS based on the count results, obtain a cell suspension (density 7 × 107 / mL), and put them in an ice box. Put it in and prepare for use.
7.3.2 Cell inoculation, tumor survey a, prior to inoculation, mark nude mice with rat / mouse ear tags and disinfect the skin at the inoculation site with 75% medical alcohol.
b. When inoculating, mix the cell suspension evenly, suck 0.1-1 mL of cell suspension with a 1 mL syringe, remove air bubbles, then place the syringe in an ice bag for use. Prepare for.
c. Inoculate the test nude mice in sequence (with the inoculation site on the right side of the back of the nude mouse near the right shoulder, 0.1 mL of cell suspension is subcutaneously inoculated).
7.3.3 Tumor measurement, grouping, administration a, and tumor growth status of tumor-bearing mice are used to measure the tumor 14-16 days after inoculation and calculate the size of the tumor.
Tumor volume calculation: Tumor volume (mm3) = length (mm) x width (mm) x width (mm) / 2
b. Group by random grouping based on tumor size.
c. Based on the grouping results, the test drug (administration method: oral administration, administration dose: 30 mg / kg, administration volume: 10 mL / kg, administration frequency: 2 times / day, administration cycle: 14 days, solvent: 0. Start administration of 5% CMC / 1% Tween 80).
d. After administration of the test drug, the tumor is weighed twice every two weeks.
e, euthanize the animal after the experiment is complete.

7.4 Test data:

7.5 Experimental Results As can be seen from the above results, the above-mentioned examples of this patent have an excellent tumor suppression rate.

Claims (26)

A compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof.

(During the ceremony
X ₁ is-(CR ₃ R ₄ ) m _1- , X ₂ is-(CR ₅ R ₆ ) m _2- , X ₃ is-(CR ₇ R ₈ ) m _3- .
Y is selected from O or S,
Z is selected from NX ₄ , O or S,
X ₄ is hydrogen,
R is selected from hydrogen, deuterium or halogen ,
R ₁ is hydrogen, deuterium, halogen, hydroxy group, mercapto group, cyano group, nitro group, azide group, C _1-8 alkyl group, C _2-8 alkenyl group, C _2-8 alkynyl group, C _3-8 . Cycloalkyl group, 3-8 membered heterocyclic group, 3-8 membered heterocyclic oxy group, 3-8 membered heterocyclic thio group, -C _0-8 -S (O) _r R ₉ , -C _0-8- OR _{10, -C 0-8-C (O) OR 10 , -C 0-8 - C} (O) R ₁₁ , -C _0-8 -OC (O) R ₁₁ , -C _0- From ₈ -NR ₁₂ R ₁₃ , -C _0-8 -C (O) NR ₁₂ R ₁₃ , -N (R ₁₂ ) -C (O) R ₁₁ or -N (R ₁₂ ) -C (O) OR ₁₀ . Chosen,
Further, in some cases, halogen, hydroxy group, alkyl group, alkoxy group, halo-substituted C _1-8 alkyl group, C _3-8 cycloalkyl group, 3-8 member heterocyclic group, 3-8 member heterocyclic oxy group, 3-8-membered heterocyclic thio group, C _1-8 alkoxy-substituted 3-8-membered heteroaryl group, -C _0-8 -S (O) _r R ₉ , -C _0-8 -OR ₁₀ or -C It may be substituted with one or more substituents selected from _0-8 -NR ₁₂ R ₁₃ .
R ₂ is selected from cyano or thiocyanate groups
R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , and R ₈ are independently hydrogen, dehydrogen, halogen, C _1-8 alkyl group, C _2-8 alkoxy group, C _2-8 alkynyl group, respectively. Halo-substituted C _1-8 alkyl group, C _3-8 cycloalkyl group, 3-8-membered heterocyclic group, C _1-8 alkoxy group, halo-substituted C _1-8 alkoxy group, C _3-8 cycloalkoxy group or 3 Selected from -8-membered heterocyclic oxy groups,
Alternatively, R ₃ and R ₄ , R ₅ and R ₆ , R ₇ and R ₈ form a 3-5 membered cycloalkyl group or 3-5 membered heterocycle with the directly bonded carbon atom.
R ₉ is hydrogen, dehydrogen, C _1-8 alkyl group, C _2-8 alkenyl group, C _3-8 cycloalkyl group, 3-8 member heterocyclic group, halo-substituted C _1-8 alkyl group, phenyl group, Selected from p-methylphenyl group, amino group, mono-C _1-8 alkylamino group, diC _1-8 alkylamino group or C _1-8 alkanoylamino group.
R ₁₀ is hydrogen, deuterium, C _1-8 alkyl group, C _3-8 cycloalkyl group, C _5-10 aryl group, 3-8 member heterocyclic group, halo-substituted C _1-8 alkyl group or hydroxy-substituted C. Selected from _1-8 alkyl groups,
R ₁₁ is hydrogen, dehydrokyl, C _1-8 alkyl group, C _1-8 alkoxy group, C _3-8 cycloalkyl group, C _3-8 cycloalkoxy group, halo-substituted C _1-8 alkyl group, halo-substituted C. Selected from _1-8 Alkoxy Group, Hydroxy Substituted C _1-8 Alkyl Group or Hydroxy Substituted C _1-8 Alkoxy Group
R ₁₂ and R ₁₃ are independently hydrogen, deuterium, C _1-8 alkyl group, C _1-8 alkoxy C _1-8 alkyl group, C _3-8 cycloalkyl C _1-8 alkyl group, C _2- Select from ₈ -alkenyl group, C _2-8 alkynyl group, C _3-8 cycloalkyl group, 3-8 member heterocyclic group, C _5-10 aryl group, 5-10 member heteroaryl group or C _1-8 alkanoyl group. Re,
m ₁ is 2, m ₂ is 2, m ₃ is 0, or m ₁ is 2, m ₂ is 1, m ₃ is 1.
r is 0, 1 or 2. ) The compound according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which is selected from the compounds of the following formula (II).

(During the ceremony
A ₁ is selected from binding, NX ₄ , O or S,
B ₁ is selected from bond, O or ring, the ring being a C _3-8 cycloalkyl group, a 3-8 member heterocyclic group, a C _3-8 cycloalkyl C _1-8 alkyl group, a C _5-10 aryl group. Or selected from 5-10 member heteroaryl groups ,
R ₁₄ is hydrogen, halogen, C _1-8 alkyl group, halo-substituted C _1-8 alkyl group, C _1-8 alkoxy group, C _3-8 cycloalkyl group, 3-8 member heterocyclic group, 3-8 member. From heterocyclic oxy group, 3-8 membered heterocyclic thio group, -C _0-8 -S (O) _r R ₉ , -C _0-8 -OR ₁₀ or -C _0-8 -NR ₁₂ R ₁₃ Chosen,
R ₁₅ and R ₁₆ are independently hydrogen, halogen, hydroxy group, alkyl group, halo-substituted C _1-8 alkyl group, C _3-8 cycloalkyl group, 3-8 member heterocyclic group, 3-8 member complex. Select from ring oxy group, 3-8 member heterocyclic thio group, -C _0-8 -S (O) _r R ₉ , -C _0-8 -OR ₁₀ or -C _0-8 -NR ₁₂ R ₁₃ Re,
Alternatively, R ₁₅ and R ₁₆ form a cycloalkyl group or a heterocyclic group together with a directly bonded carbon atom, and the alkyl group or heterocyclic group may further form a C _1-8 alkyl group or a C _1-8 haloalkyl group. It may be substituted with one or more substituents selected from groups, halogens, hydroxy groups, C _1-8 alkoxy groups and C _1-8 hydroxyalkyl groups.
n is selected from 0-4,
Z, Y, X ₁ -X ₃ , R and R ₂ are as described in claim 1. ) R is selected from hydrogen or fluorine,
R ₂ is selected from cyano or thiocyanate groups
B ₁ is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, an oxetanyl group, a thietanyl group, an azetidineyl group, a furanyl group, a thienyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a pyridyl group, an oxazolyl group, a thiazolyl group, a tetrahydrofuranyl group, Selected from a tetrahydrothienyl group, a tetrahydropyrrrolyl group, a tetrahydroimidazolyl group, a tetrahydropyranyl group, a piperazinyl group or a morpholinyl group,
R ₁₄ is selected from hydrogen, fluorine, chlorine, methoxy group, ethoxy group, trifluoromethyl group or cyclopropyl group.
When -R ₁₄ and-(CR ₁₅ R ₁₆ ) _n -are bonded to the adjacent ring atom of B ₁ , the stereoisomers are (R) -R ₁₄ and (S)-(CR ₁₅ R ₁₆ ) _n- . , (S) -R ₁₄ and (R)-(CR ₁₅ R ₁₆ ) _n- , (R) -R ₁₄ and (R)-(CR ₁₅ R ₁₆ ) _n -or (S) -R ₁₄ and (S) )-(CR ₁₅ R ₁₆ ) _n -includes the configuration of
When −R ₁₄ and − (CR ₁₅ R ₁₆ ) _n − are bonded to the common ring atom of B ₁ , the stereoisomers are (R) −R ₁₄ and (S) − (CR ₁₅ R ₁₆ ) _n . -Or includes the conformation of (S) -R ₁₄ and (R)-(CR ₁₅ R ₁₆ ) _n- .
The compound according to claim 2, a stereoisomer thereof, or a pharmacy thereof, wherein Z, Y, X ₁ -X ₃ , A ₁ , and R _15-16 are as described in claim 2. Tolerable salt. The compound according to claim 3, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which is selected from the following compounds .

R is selected from hydrogen or fluorine,
R ₂ is selected from cyano or thiocyanate groups
B ₁ is selected from phenyl or pyridyl groups
R ₁₄ is selected from fluorine, chlorine, methoxy group, ethoxy group, trifluoromethyl group or cyclopropyl group.
n is chosen from 0 or 1
When -R ₁₄ and -A _1- are bonded to the adjacent carbon atoms of the benzene ring, the stereoisomers are (R) -R ₁₄ and (S) -A _1- , (S) -R ₁₄ and ( Includes the conformation of R) -A _1- , (R) -R ₁₄ and (R) -A _1- or (S) -R ₁₄ and (S) -A _1- .
The compound according to claim 2, a stereoisomer thereof, wherein Z, Y, X ₁ -X ₃ , A ₁ , R ₁ and R _15-16 are as described in claim 2. Or its pharmaceutically acceptable salt. The compound according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which is selected from the compounds of the following formula (III).

(During the ceremony
A ₂ is selected from binding, NX ₄ , O or S,
B ₂ is selected from a C _1-8 alkyl group, a C _1-8 alkoxy group, and a C _1-8 alkoxy C _1-8 alkyl group.
R is selected from hydrogen, deuterium or halogen ,
R ₁₇ is hydrogen, C _1-8 alkyl group, halogen, halo-substituted C _1-8 alkyl group, C _3-8 cycloalkyl group, 3-8 member heterocyclic group, 3-8 member heterocyclic oxy group, 3- 8-membered heterocyclic thio group, -C _0-8 -S (O) _r R ₉ , -C _0-8 -OR ₁₀ , -C _0-8 -C (O) OR ₁₀ , -C _0-8 -C (O) R ₁₁ , -C _0-8 -OC (O) R ₁₁ , -C _0-8 -NR ₁₂ R ₁₃ , -C _0-8 -C (O) NR ₁₂ R ₁₃ ,- Selected from N (R ₁₂ ) -C (O) R ₁₁ or -N (R ₁₂ ) -C (O) OR ₁₀
R ₁₈ and R ₁₉ are independently selected from halogen, hydroxy group, C _1-8 alkyl group or halo-substituted C _1-8 alkyl group, respectively.
Alternatively, R ₁₈ and R ₁₉ form a cycloalkyl group or a heterocyclic group together with a directly bonded carbon atom, and the cycloalkyl group or the heterocyclic group may further form a C _1-8 alkyl group or a C _1-8 . It may be substituted with one or more substituents selected from haloalkyl groups, halogens, hydroxy groups, C _1-8 alkoxy groups and C _1-8 hydroxyalkyl groups.
n is selected from 0-4. ) R is selected from hydrogen or fluorine,
R ₂ is selected from cyano or thiocyanate groups
B ₂ is selected from a methyl group, an ethyl group, a methoxy group, an ethoxy group, a methoxyethyl group, an ethoxymethyl group or an ethoxyethyl group.
R ₁₇ is hydrogen, methyl group, methoxy group, ethoxy group, isopropoxy group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclopropoxy group, cyclobutoxy group, cyclopentoxy group, furanyl group, thienyl group, pyrrolyl group, Selected from imidazolyl group, tetrahydrofuranyl group, tetrahydrothienyl group, tetrahydropyrrrolyl group, tetrahydroimidazolyl group, piperazinyl group or morpholinyl group,
R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , and R ₈ are independently derived from hydrogen, dehydrogen, fluorine, chlorine, methyl group, ethyl group, isopropyl group, methoxy group, ethoxy group or isopropoxy group, respectively. The compound according to claim 6, characterized in that it is selected, a steric isomer thereof or a pharmaceutically acceptable salt thereof. The compound according to claim 7, characterized in that it is selected from the following compounds , a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

R is selected from hydrogen or fluorine,
R ₂ is selected from cyano or thiocyanate groups
B ₂ is selected from a methyl group, an ethyl group, a methoxy group, an ethoxy group, a methoxyethyl group, an ethoxymethyl group or an ethoxyethyl group.
R ₁₇ is a methyl group, a methoxy group, an ethoxy group, an isopropoxy group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a furanyl group, a thienyl group, a pyrrolyl group, an imidazolyl group, a tetrahydrofuranyl group, a tetrahydrothienyl group, a tetrahydropyrrrolyl group. , Tetrahydroimidazolyl group, piperazinyl group or morpholinyl group,
The compound according to claim 6, wherein R ₃ and R ₄ , R ₅ and R ₆ , and R ₇ and R ₈ form a cyclopropyl group or a cyclobutyl group together with a directly bonded carbon atom. The stereoisomer or a pharmaceutically acceptable salt thereof. R is selected from hydrogen or fluorine,
R ₁ is selected from hydrogen, deuterium, furanyl group, thienyl group, pyrrolyl group, pyrazolyl group, imidazolyl group, azetidinel group, tetrahydrofuranyl group, tetrahydrothienyl group, tetrahydropyrrolyl group, tetrahydropyrazolyl group or tetrahydroimidazolyl group.
In some cases, further, halogen, hydroxy group, alkyl group, halo-substituted C _1-8 alkyl group, C _3-8 cycloalkyl group, 3-8 member heterocyclic group, 3-8 member heterocyclic oxy group, 3-8. Member heterocyclic thio group, -C _0-8 -S (O) _r R ₉ , -C _0-8 -OR ₁₀ , -C _0-8 -C (O) OR ₁₀ , -C _0-8- C (O) R ₁₁ , -C _0-8 -OC (O) R ₁₁ , -C _0-8 -NR ₁₂ R ₁₃ , -C _0-8 -C (O) NR ₁₂ R ₁₃ , -N It may be substituted with one or more substituents selected from (R ₁₂ ) -C (O) R ₁₁ or -N (R ₁₂ ) -C (O) OR ₁₀ .
The compound according to claim 1, wherein R ₂ is selected from a cyano group, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The compound according to claim 10, characterized in that it is selected from the following compounds , a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

The compound according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which is selected from the compounds of the following formula (IV).

(During the ceremony
Z, Y, A ₁ , B ₁ , X ₁ -X ₃ , R ₁₄ -R ₁₆ or n are as described in claim 2. ) The compound according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which is selected from the compounds of the following formula (V).

(During the ceremony
Ring C is selected from C _3-8 cycloalkyl groups, 3-8 membered heterocyclic groups, C _5-10 aryl groups or 5-10 membered heteroaryl groups, and u is 0, 1, 2, 3, 4 or 5 and
Z, A ₁ , X ₁ -X ₃ , R ₁₄ -R ₁₆ or n are as described in claim 2. ) The compound according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which is selected from the compounds of the following formula (VI).

(During the ceremony
X ₁ is-(CR ₃ R ₄ ) m _1- , X ₂ is-(CR ₅ R ₆ ) m _2- , X ₃ is-(CR ₇ R ₈ ) m _3- .
R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , and R ₈ are independently hydrogen, dehydrogen, halogen, hydroxy group, carboxyl group, amino group, C _1-8 alkyl group, halo-substituted C _1- Selected from ₈ alkyl groups, C _3-8 cycloalkyl groups, C _1-8 alkoxy groups or halo-substituted C _1-8 alkoxy groups.
Alternatively, R ₃ and R ₄ , R ₅ and R ₆ , R ₇ and R ₈ form a cycloalkyl group or heterocyclic group together with the directly bonded carbon atom, and the cycloalkyl group or heterocyclic group may optionally form a cycloalkyl group or heterocyclic group. Further, even if it is substituted with one or more substituents selected from a C _1-8 alkyl group, a C _1-8 haloalkyl group, a halogen, a hydroxy group, a C _1-8 alkoxy group and a C _1-8 hydroxyalkyl group. Often,
Z, A ₁ and m ₁ -m ₃ are as described in claim 2.
R ₁₇ -R ₁₉ and n are as described in claim 6. ) The compound according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which is selected from the compounds of the following formula (VII).

(During the ceremony
Z, A ₁ , B ₁ , X ₂ , X ₃ , R ₁₄ -R ₁₆ or n are as described in claim 2. ) The compound according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which is selected from the compounds of the following formula (VIII).

(During the ceremony
Z, A ₁ , X ₂ , X ₃ , R ₁₇ -R ₁₉ or n are as described in claim 1. ) The compound according to claim 1, which is selected from the compounds of the following formula (IX), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

(During the ceremony
Ring D is selected from C _3-8 cycloalkyl groups, 3-8 membered heterocyclic groups, C _5-10 aryl groups or 5-10 membered heteroaryl groups.
R is selected from hydrogen or fluorine,
R ₂ is selected from cyano groups
u is 0, 1, 2, 3, 4 or 5
Z, Y, X1 _- X3 _, and R14 are as described _in claim 4. ) R ₁₄ is hydrogen, C _1-8 alkyl group, C _1-8 alkoxy group, halo-substituted C _1-8 alkyl group, C _3-8 cycloalkyl group, 3-8 member heterocyclic group, 3-8 member heterocycle. Oxy group, 3-8 member heterocyclic thio group, -C _0-8 -S (O) _r R ₉ , -C _0-8 -OR ₁₀ , -C _0-8 -C (O) OR ₁₀ , -C _0-8 -C (O) R ₁₁ , -C _0-8 -OC (O) R ₁₁ , -C _0-8 -NR ₁₂ R ₁₃ , -C _0-8 -C (O) NR ₁₂ The compound according to claim 2, wherein the compound is selected from R ₁₃ , -N (R ₁₂ ) -C (O) R ₁₁ or -N (R ₁₂ ) -C (O) OR ₁₀ . A steric isomer or a pharmaceutically acceptable salt thereof. R ₁₇ is hydrogen, C _1-8 alkyl group, C _1-8 alkoxy group, halo-substituted C _1-8 alkyl group, C _3-8 cycloalkyl group, 3-8 member heterocyclic group, 3-8 member heterocycle. Selected from an oxy group and a 3-8-membered heterocyclic thio group, the C _1-8 alkyl group, C _1-8 alkoxy group, halo-substituted C _1-8 alkyl group, C _3-8 cycloalkyl group, 3-8. The membered heterocyclic group, 3-8 membered heterocyclic oxy group and 3-8 membered heterocyclic thio group may be C _1-8 alkyl group, C _1-8 alkoxy group, halo-substituted C _1-8 alkyl group, C. The compound according to claim 6, a steric isomer thereof or a pharmaceutically acceptable salt thereof, which may be further substituted with a _3-8 cycloalkyl group and a 3-8 member heterocyclic group. .. A compound selected from the following compounds, its stereoisomer or a pharmaceutically acceptable salt thereof.

A method for producing a compound according to any one of claims 1-20, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which comprises the following steps.

(During the ceremony
X ₁ , X ₂ , X ₃ , R, R ₁ , R ₂ , Z and Y are as defined in claim 1, and Pg is a hydroxy protecting group. ) 21. The method of claim 21, wherein the Pg is a C _1-8 alkyl or benzyl group. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1-20, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Use of the compound according to any one of claims 1-20, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 23 in the production of a FGFR4 inhibitor drug. Use of the compound according to claim 1-20, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition according to claim 23 in the manufacture of a therapeutic agent for cancer. The use according to claim 25, wherein the cancer is liver cancer, gastric cancer, prostate cancer, skin cancer, ovarian cancer, lung cancer, breast cancer, colon cancer, glioma or rhabdomyomyoma.